Hartmut Derendorf
University of Florida, Pharmaceutics, Faculty Member
- Hartmut Derendorf is Distinguished Professor Emeritus in the Department of Pharmaceutics at the University of Florida... moreHartmut Derendorf is Distinguished Professor Emeritus in the Department of Pharmaceutics at the University of Florida College of Pharmacy in Gainesville. He also served as the 18th University of Florida Distinguished Alumni Professor. Prof. Derendorf has published over 500 scientific publications and ten textbooks in English and German. He is Editor or Associate Editor of five Journals such as the Journal of Clinical Pharmacology. Prof. Derendorf has served as President of the American College of Clinical Pharmacology (ACCP) and President of the International Society of Antiinfective Pharmacology (ISAP). He was awarded the Distinguished Research Award, the Mentorship Award and the Nathaniel T. Kwit Distinguished Service Award of ACCP, the Research Achievement Award in Clinical Science of the American Association of Pharmaceutical Sciences (AAPS), the Leadership Award of the International Society of Pharmacometrics (ISOP), the Volwiler Award of the American Association of Colleges of Pharmacy (AACP) and the Mentor Award of the American Society for Clinical Pharmacology and Therapeutics (ASCPT).edit
Beverage-drug interactionshave remained an active area of research and have been the subject of extensive investigations in the past two decades. The known mechanismsof clinically relevant beverage-drug interactions include modulation of... more
Beverage-drug interactionshave remained an active area of research and have been the subject of extensive investigations in the past two decades. The known mechanismsof clinically relevant beverage-drug interactions include modulation of the activity of cytochrome P450 (CYP) 3A and organic anion transporting polypeptide (OATP). For CYP3A-mediated beverage-drug interaction, the in vivo CYP3A inhibitory effect is limited to grapefruit juice (GFJ), which increases the bioavailability of several orally administered drugs that undergo extensive first-pass metabolism via enteric CYP3A. In contrast, clinically significant OATP-mediated beverage-drug interactions have been observed with not only GFJ, but also orange juice, apple juice, and most recently, green tea. Fruit juices and green tea are all a mixture of a large number of constituents. The investigation on specific constituent(s) responsible for the enzyme and/or transporter inhibition remains an active area of research and many new...
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ABSTRACT Pharmacometrics plays an important role in rational dosing design of antimicrobial therapy by defining the relationship between dose, dosing interval, drug concentration, bacterial response, infection outcome, and toxicity, as... more
ABSTRACT Pharmacometrics plays an important role in rational dosing design of antimicrobial therapy by defining the relationship between dose, dosing interval, drug concentration, bacterial response, infection outcome, and toxicity, as well as the variability surrounding these variables. Modeling and simulation is becoming more extensively used to characterize antimicrobial strategies to combat emergence of drug-resistant bacteria, which is imposing a high cost on patient survivability and the overall health-care system. In this chapter, we discuss how pharmacometric approaches are being utilized to tackle these challenges. The approaches in designing treatment strategies using minimum inhibitory concentrations and in vitro time course of bacterial killing are explained to provide a thorough overview of the current state-of-the-art exploration of antimicrobial pharmacokinetic–pharmacodynamic (PKPD) modeling and simulation. In turn, the information from in vitro and animal studies is connected with clinical outcome for the purpose of determining key information that can improve therapeutic success in the clinic. This chapter also discusses the strategies for optimized dosing regimens and combination therapies that are currently explored to tackle the challenges posed by development of drug-resistant infections.
The aim of this paper was to analyze the impact of anesthesia induced by urethane on pharmacokinetics (PK) parameters of fluconazole (FCZ), mostly eliminated via renal excretion and voriconazole (VRC), eliminated mainly by hepatic... more
The aim of this paper was to analyze the impact of anesthesia induced by urethane on pharmacokinetics (PK) parameters of fluconazole (FCZ), mostly eliminated via renal excretion and voriconazole (VRC), eliminated mainly by hepatic metabolism. FCZ and VRC PK were investigated after administration of 10 mg/kg i.v. and 5 mg/kg i.v. doses to awake and urethane anesthetized Wistar rats (n = 6 per group), respectively. After dosing, blood samples were collected up to 18 h (FCZ) or 12 h (VRC) and the plasma data analysis was performed using the software MONOLIX v. 4.2.2. The population PK parameters and microconstants were determined by fitting plasma concentration-time profiles to two-compartment model for FCZ and three-compartment model for VRC. Fitting of FCZ plasma profiles after dosing to awake and anaesthetized animals resulted in a volume of distribution (V) of 9.3 and 8.1 L/kg, and k10 values of 0.12 and 0.14 h(-1) , respectively. VRC plasma profiles in awake and anaesthetized showed V 8.7 of and 7.6 L/kg, and k10 of 0.15 and 0.16 h(-1) , respectively. No statistical differences between plasma PK parameters and microconstants for the same drug in both animal conditions studied were observed (α = 0.05). © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
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The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired... more
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis prompted the reintroduction of para-aminosalicylic acid (PAS) to protect companion anti-tuberculosis drugs from additional acquired resistance. In sub-Saharan Africa, MDR/XDR tuberculosis with HIV coinfection is common, and concurrent treatment of HIV infection and MDR/XDR tuberculosis is required. Out of necessity, patients receive multiple drugs, and PAS therapy is frequent; however, neither potential drug interactions nor the effects of HIV infection are known. Potential drug-drug interaction with PAS and the effect of HIV infection was examined in 73 pulmonary tuberculosis patients; 22 (30.1%) were HIV coinfected. Forty-one pulmonary MDR or XDR tuberculosis patients received 4 g PAS twice daily, and in a second crossover study, another 32 patients were randomized, receiving 4 g PAS twice daily or 8 g PAS once daily. A PAS population pharmacokinetic model in two dosing regim...
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Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available... more
Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available because of inhaled bioavailability. In healthy subjects this may lead to measurable systemic effects, such as cortisol reduction. A clinical study was conducted in 12 healthy volunteers to determine the systemic effects after inhaled administration of single 500-micrograms, 1,000-micrograms, and 2,000-micrograms doses of FP. Blood samples were collected over a 24-hour period after administration. Concentrations of FP and cortisol were measured in plasma by immunoassay. Cortisol reduction was chosen as the pharmacodynamic parameter. A novel linear release rate model was used to parameterize the cortisol data. The pharmacokinetics of FP were linear over the dose range studied. The cortisol release parameters were determined from baseline data (before drug a...
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For assessing antibiotic effects, the minimum inhibitory concentration (MIC) neglects that most antibiotics display different rates of bacterial killing. Time-kill curves, on the other hand, provide details on these killing rates but... more
For assessing antibiotic effects, the minimum inhibitory concentration (MIC) neglects that most antibiotics display different rates of bacterial killing. Time-kill curves, on the other hand, provide details on these killing rates but their interpretation is more complex and hardly standardised. The aim of the present study was to develop an analysis method to easily compare the pharmacodynamics of linezolid (LZD) against Staphylococcus aureus and Enterococcus faecium via in vitro time-kill curve experiments and to describe it by mathematical modelling. The effect of LZD against both organisms was investigated in a static in vitro infection model using 0.5-32.0 μg/mL LZD over 24h. LZD concentrations were quantified by a validated HPLC assay. A modified sigmoidal maximum effect (Emax) pharmacokinetic/pharmacodynamic (PK/PD) model that accounts for time-dependent effects was developed in 'R'. As a continuous, growth-control-normalised pharmacodynamic measure, the relative bacte...
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The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs,... more
The degree of systemic exposure ofter inhalation of corticosteroids is of great clinical concern. For optimum outcome, the pulmonary deposition should be sufficiently high to produce the desired anti-inflammatory effect in the lungs, whereas the plasma concentrations due to the absorption of the corticosteroid from the lung and the gut should be minimal. Recently, it has been reported that inhaled mometasone furoate has a systemic bioavailability of less than 1%, which is much lower than other corticosteroids currently available. However, critical evaluation of the study methodology and results does not support this finding. A major shortfall of the study was an insufficient analytical sensitivity, resulting in a calculated average plasma concentration profile that was entirely below the limit of quantification. These numbers were generated by replacing all concentrations below the limit of quantification byzero and then calculating an average value. This procedure can lead to erron...
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Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting... more
Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially ben...
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Patients with predominantly upper body obesity are at greater risk for developing diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Little is known about the mechanisms involved in the regulation of regional... more
Patients with predominantly upper body obesity are at greater risk for developing diabetes mellitus, hyperlipidemia, hypertension, and cardiovascular disease. Little is known about the mechanisms involved in the regulation of regional body distribution. It has been accepted that the accumulation of fat into adipose tissue depends on regional metabolic regulation of adipocytes and that glucocorticoids play a role in this mechanism. The aim of the present study is to investigate how the pharmacokinetics of cortisol correlate to intraabdominal and subcutaneous fat distribution in obese patients. A group of 24 obese patients (13 males and 11 females) were submitted to a CT scan for intraabdominal and subcutaneous fat area evaluation. A 30-min cortisol infusion (0.25 mg/kg) was administered and plasma cortisol was measured over 6 hours. Patients with larger intraabdominal fat areas were found to have a higher cortisol clearance than those with lower intraabdominal fat areas. Cortisol cle...
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Microdialysis is a suitable method to monitor unbound concentrations of antimicrobial drugs in the interstitial tissue space which is the site of many infections. The aim of this investigation was to examine whether free tissue levels of... more
Microdialysis is a suitable method to monitor unbound concentrations of antimicrobial drugs in the interstitial tissue space which is the site of many infections. The aim of this investigation was to examine whether free tissue levels of cefodizime (81% plasma protein binding) and cefpirome (10% plasma protein binding) in muscle and subcutaneous adipose tissue of healthy volunteers obtained by microdialysis are consistent with the extent of their respective plasma protein binding. Healthy volunteers were given cefodizine and cefpirome at a single intravenous 2-g dose in a randomized crossover design. Microdialysis probes were inserted into a medial vastus muscle and into the periumbilical subcutaneous layer. After calibration of the probe, samples of serum and microdialysis fluid were obtained and drug concentrations were measured using a microagar diffusion-bioassay. There was a reasonable agreement between plasma protein binding data and the tissue penetration of both cephalospori...
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Methylprednisolone in the form of its hemisuccinate ester was injected intravenously in doses of 10 mg/kg and 63.1 mg. Plasma levels of methylprednisolone and of the ester were measured and their kinetics were calculated. Results indicate... more
Methylprednisolone in the form of its hemisuccinate ester was injected intravenously in doses of 10 mg/kg and 63.1 mg. Plasma levels of methylprednisolone and of the ester were measured and their kinetics were calculated. Results indicate dose dependency in the kinetics of both. About 10% of the dose was excreted unchanged as hemisuccinate in the urine, indicating incomplete conversion of the prodrug. When methylprednisolone (80 mg) was also taken by mouth, the relative bioavailability of the tablets was 99%. Saliva levels of methylprednisolone were low but paralleled plasma levels in the postdistribution phase. No methylprednisolone hemisuccinate was found in saliva.
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To prove the clinical usefulness of cortisol measurements in saliva for the exact assessment of a patient's corticoid status under therapeutic hormone substitution, we measured simultaneously total cortisol in serum and... more
To prove the clinical usefulness of cortisol measurements in saliva for the exact assessment of a patient's corticoid status under therapeutic hormone substitution, we measured simultaneously total cortisol in serum and non-protein-bound cortisol in saliva after administration of different forms of hydrocortisone (cortisol) in eight cortisol-suppressed, healthy male volunteers. The intravenous and oral administration of 20 mg of cortisol exceeds the binding capacity of the corticosteroid-binding globulin (CBG), leading to an increase of the ratio between salivary and serum cortisol at the higher cortisol concentrations in blood. After rectal administration of 100 mg of cortisol acetate, the serum cortisol concentration does not exceed the binding capacity of CBG, so the ratio between salivary and serum cortisol remains nearly constant. However, this ratio was higher after rectal administration than after intravenous and oral administration, probably because of weaker binding of ...
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A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled... more
A better understanding of second-line drug (SLD) pharmacokinetics, including cavitary penetration, may help optimize SLD dosing. Patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) undergoing adjunctive surgery were enrolled in Tbilisi, Georgia. Serum was obtained at 0, 1, 4, and 8 h and at the time of cavitary removal to measure levofloxacin concentrations. After surgery, microdialysis was performed using theex vivocavity, and levofloxacin concentrations in the collected dialysate fluid were measured. Noncompartmental analysis was performed, and a cavitary-to-serum levofloxacin concentration ratio was calculated. Twelve patients received levofloxacin for a median of 373 days before surgery (median dose, 11.8 mg/kg). The median levofloxacin concentration in serum (Cmax) was 6.5 μg/ml, and it was <2 μg/ml in 3 (25%) patients. Among 11 patients with complete data, the median cavitary concentration of levofloxacin was 4.36 μg/ml (range, 0.46 to 8.82). The median cavita...
Research Interests: Microbiology, Medical Microbiology, Adolescent, Humans, Female, and 5 moreMale, Young Adult, Middle Aged, Adult, and Levofloxacin
AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical... more
AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of...
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The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism,... more
The liver is a complex organ with great ability to influence drug pharmacokinetics. Due to its wide array of function, its impairment has the potential to affect bioavailability, enterohepatic circulation, drug distribution, metabolism, clearance, and biliary elimination. These alterations differ widely depending on the cause of the liver failure, if it is acute or chronic in nature, the extent of impairment, and comorbid conditions. In addition, effects on liver functions do not occur in a proportional or predictable manner for escalating degrees of liver impairment. The ability of hepatic alterations to influence PK is also dependent on drug characteristics, such as administration route, chemical properties, protein binding, and extraction ratio, among others. This complexity makes it difficult to predict what these effects have on drugs. Unlike certain classes of agents, efficacy of anti-infectives is most often dependent on fulfilling pharmacokinetic/pharmacodynamic targets, suc...
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Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We... more
Rifapentine is highly protein bound in blood, but the free, unbound drug is the microbiologically active fraction. In this exploratory study, we characterized the free plasma fraction of rifapentine in 41 patients with tuberculosis. We found a lower total rifapentine concentration but significantly higher free rifapentine levels in African patients of black race compared to non-Africans. These data support larger pharmacokinetic/pharmacodynamic studies to confirm these findings and assess free rifapentine in relation to microbiological and clinical outcomes.
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Inhaled corticosteroids play a pivotal role in the treatment of asthma. Inhalation permits effective delivery of the corticosteroid in high concentration to target sites within the lung while minimizing systemic exposure. Consequently,... more
Inhaled corticosteroids play a pivotal role in the treatment of asthma. Inhalation permits effective delivery of the corticosteroid in high concentration to target sites within the lung while minimizing systemic exposure. Consequently, the safety profile of inhaled corticosteroids is markedly better than that of oral corticosteroid therapy. However, although it was first thought that direct delivery might eliminate systemic adverse effects, this has not been confirmed by clinical trials and experience. Inhaled corticosteroids are absorbed from the lungs into the systemic circulation, in which they can acutely decrease growth velocity in children, an effect that fortunately appears to be temporary and might have no effect on final adult height. In sufficient dosages, they also produce bone mineral loss leading to osteoporosis and might increase the risk of cataracts, glaucoma, skin atrophy, and vascular changes that increase the risk of ecchymoses. Effective evaluation of the severit...
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Moxifloxacin is reported to have increased distribution into the prostate compared with older fluoroquinolones such as norfloxacin and ciprofloxacin, being able to reach tissue-to-plasma concentration ratios greater than unity. However,... more
Moxifloxacin is reported to have increased distribution into the prostate compared with older fluoroquinolones such as norfloxacin and ciprofloxacin, being able to reach tissue-to-plasma concentration ratios greater than unity. However, most of these studies use tissue homogenates derived from biopsy samples, which can lead to overestimation of free concentrations as fluoroquinolones tend to accumulate in the intracellular space. The aim of this study was to investigate moxifloxacin pharmacokinetics in rat prostate interstitial fluid by microdialysis. Tissue pharmacokinetics was assessed by implanting a small microdialysis catheter in the prostate gland. Blood samples were simultaneously collected for assessing plasma pharmacokinetics. Analysis of plasma (N=154) and microdialysis (N=344) concentrations after a single intravenous dose of 6 or 12mg/kg moxifloxacin was conducted in the non-linear mixed-effect modelling software NONMEM v.6 as well by a non-compartmental approach. Moxifloxacin showed a significant tissue distribution in the prostate (AUCprostate,ISF/fu·AUCplasma=1.24±0.37), 59% higher than the value obtained for levofloxacin in a previous study. A three-compartment model with non-linear kinetics could adequately describe moxifloxacin pharmacokinetics in terms of curve fitting and precision in parameter estimation. The developed pharmacokinetic model indicates that passive diffusion and active transport are the mechanisms involved in moxifloxacin distribution to the prostate. These findings suggest that moxifloxacin could be a better alternative to levofloxacin for the treatment of chronic bacterial prostatitis owing to its enhanced tissue penetration and higher AUCtissue/MIC ratios, even though it is not yet approved by the US FDA for this indication.
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Extracts from artichoke leaves are traditionally used in the treatment of dyspeptic and hepatic disorders. Various potential pharmacodynamic effects have been observed in vitro for mono- and dicaffeoylquinic acids (e.g. chlorogenic acid,... more
Extracts from artichoke leaves are traditionally used in the treatment of dyspeptic and hepatic disorders. Various potential pharmacodynamic effects have been observed in vitro for mono- and dicaffeoylquinic acids (e.g. chlorogenic acid, cynarin), caffeic acid and flavonoids (e.g. luteolin-7-O-glucoside) which are the main phenolic constituents of artichoke leaf extract (ALE). However, in vivo not only the genuine extract constituents but also their metabolites may contribute to efficacy. Therefore, the evaluation of systemic availability of potential bioactive plant constituents is a major prerequisite for the interpretation of in vitro pharmacological testing. In order to get more detailed information about absorption, metabolism and disposition of ALE, two different extracts were administered to 14 healthy volunteers in a crossover study. Each subject received doses of both extracts. Extract A administered dose: caffeoylquinic acids equivalent to 107.0 mg caffeic acid and luteolin glycosides equivalent to 14.4 mg luteolin. Extract B administered dose: caffeoylquinic acids equivalent to 153.8 mg caffeic acid and luteolin glycosides equivalent to 35.2 mg luteolin. Urine and plasma analysis were performed by a validated HPLC method using 12-channel coulometric array detection. In human plasma or urine none of the genuine target extract constituents could be detected. However, caffeic acid (CA), its methylated derivates ferulic acid (FA) and isoferulic acid (IFA) and the hydrogenation products dihydrocaffeic acid (DHCA) and dihydroferulic acid (DHFA) were identified as metabolites derived from caffeoylquinic acids. Except of DHFA all of these compounds were present as sulfates or glucuronides. Peak plasma concentrations of total CA, FA and IFA were reached within 1 h and declined over 24 h showing almost biphasic profiles. In contrast maximum concentrations for total DHCA and DHFA were observed only after 6-7 h, indicating two different metabolic pathways for caffeoylquinic acids. Luteolin administered as glucoside was recovered from plasma and urine only as sulfate or glucuronide but neither in form of genuine glucosides nor as free luteolin. Peak plasma concentrations were reached rapidly within 0.5 h. The elimination showed a biphasic profile.
Research Interests: Complementary and Alternative Medicine, Clinical Trial, Plant Biology, Flavonoids, Phytomedicine, and 15 morePhytotherapy, Humans, Female, Male, Hydrogen Production, Bioavailability, Plant extracts, Adult, Metabolic pathway, Biological Availability, Ferulic Acid, Area Under Curve, Chlorogenic Acid, Plant Leaves, and Cynara scolymus
The relationship between subjective measurements of pain (pain report and threshold of sensation) and evoked potentials following painful electrical stimulation of tooth pulp was evaluated after intake of different weak analgesics. These... more
The relationship between subjective measurements of pain (pain report and threshold of sensation) and evoked potentials following painful electrical stimulation of tooth pulp was evaluated after intake of different weak analgesics. These time-response curves for the dolorimetric parameters were correlated to the in vivo drug levels obtained in corresponding experiments by analyzing saliva. Based on the comparison between the drug levels of analgesics in saliva on the one hand and the threshold of sensation, the pain rating and changes in the amplitude of the cortical EP on the other hand, the sensitivity of the EP to changes in drug concentration was superior than to subjective pain judgement. The data were correlated to clinical pain relief investigations. The results support the suggestion of earlier research that EP evaluation may well serve as a correlate for laboratory pain.
Research Interests: Pain, Humans, Female, Male, Saliva, and 4 moreAdult, Analgesics, Dental Pulp, and Psychology and Cognitive Sciences
Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid... more
Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.
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Ceftriaxone has a very high plasma protein binding (up to 98%) that is saturable and decreases with higher concentrations. This high protein binding results in high concentrations in plasma that are frequently related to the... more
Ceftriaxone has a very high plasma protein binding (up to 98%) that is saturable and decreases with higher concentrations. This high protein binding results in high concentrations in plasma that are frequently related to the anti-infective activity. However, because only the free fraction of the drug is pharmacologically active and most of the infections are located in the tissues, it is more relevant to evaluate unbound concentrations in the interstitial space. Plasma and tissue pharmacokinetics of ceftriaxone in rats after single intravenous administration were investigated at two different concentrations (50 and 100 mg/kg). Both plasma and tissue samples were taken simultaneously from the same animal and analyzed by reversed-phase high-performance liquid chromatography. Free tissue levels in the thigh muscle were measured by microdialysis. The concentration in plasma is much higher than the free concentration in tissue. After determination of nonlinear protein binding by microdialysis and including these parameters in the pharmacokinetic model, it is possible to predict free concentrations in the interstitial space from plasma levels for any given dose.
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Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral... more
Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.
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A selective LC method with on-line post-column derivatization is described for the determination of amikacin in biological fluids. Chromatography was performed on a reversed-phase column, using pentane sulphonic acid as an ion-pairing... more
A selective LC method with on-line post-column derivatization is described for the determination of amikacin in biological fluids. Chromatography was performed on a reversed-phase column, using pentane sulphonic acid as an ion-pairing reagent. For the analysis of biological fluids, amikacin and the internal standard tobramycin were extracted using an ion exchanger (Sephadex). Following complete removal of plasma proteins, the aminoglycosides were eluted with alkaline sodium sulphate solution and injected into the chromatograph. After chromatographic separation the eluent was mixed with the derivatization reagent (o-phthalaldehyde and mercaptoethanol in borate buffer pH 10.4) in a reaction coil at 50 degrees C. Detection was performed by fluorescence (excitation: 340 nm, emission: 418 nm). The overall run time was 8 min, at a flow rate of 1.2 ml min-1. The limit of quantification was 25 ng ml-1 for amikacin in plasma.
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High-performance liquid chromatographic (HPLC) assays are described for the determination of dexamethasone phosphate, dexamethasone and hydrocortisone and for the determination of triamcinolone, triamcinolone acetonide, triamcinolone... more
High-performance liquid chromatographic (HPLC) assays are described for the determination of dexamethasone phosphate, dexamethasone and hydrocortisone and for the determination of triamcinolone, triamcinolone acetonide, triamcinolone acetonide phosphate and hydrocortisone in aqueous solutions and biological fluids. These assays allow quantification of the glucocorticoids in plasma down to a concentration of 100 ng ml(-1) (dexamethasone phosphate 300 ng ml(-1), hydrocortisone 40 ng ml(-1)). During the development of optimum extraction procedures the pK(a) values of the esters were determined by extractions performed at different pH values. The stability in vitro of the phosphate esters in ampoules, plasma and blood was studied. The esters are stable in their formulated ampoules after long-term storage, whereas the half-life in vitro of dexamethasone phosphate in plasma at 37 degrees C is 5 h and that of triamcinolone acetonide phosphate is 3.5 h. Determination by HPLC of endogenous hydrocortisone in samples from patients who received either dexamethasone phosphate or triamcinolone acetonide phosphate gave results identical with those obtained by radio-immunoassay (RIA).
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ABSTRACT
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Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit... more
Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG-CoA reductase inhibitors, calcium antagonists, and immunosuppressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P-glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.
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Medications have been taken since the first Mercury flight in 1967 and, since then, have been used for several indications such as space motion sickness, sleeplessness, headache, nausea, vomiting, back pain, and congestion. As the... more
Medications have been taken since the first Mercury flight in 1967 and, since then, have been used for several indications such as space motion sickness, sleeplessness, headache, nausea, vomiting, back pain, and congestion. As the duration of space missions get longer, it is even more likely that astronauts will encounter some of the acute illnesses that are frequently seen on Earth. Microgravity environment induces several physiological changes in the human body. These changes include cardiovascular degeneration, bone decalcification, decreased plasma volume, blood flow, lymphocyte and eosinophil levels, altered hormonal and electrolyte levels, muscle atrophy, decreased blood cell mass, increased immunoglobulin A and M levels, and a decrease in the amount of microsomal P-450 and the activity of some of its dependent enzymes. These changes may be expected to have severe implications on the pharmacokinetic and pharmacodynamic properties of drug substances.
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Inhaled glucocorticoids induce therapeutic and adverse systemic effects via the same types of receptors. Analysis of the pharmacokinetic/pharmacodynamic parameters of inhaled glucocorticoids generates a risk-benefit value (RBV). Targeted... more
Inhaled glucocorticoids induce therapeutic and adverse systemic effects via the same types of receptors. Analysis of the pharmacokinetic/pharmacodynamic parameters of inhaled glucocorticoids generates a risk-benefit value (RBV). Targeted efficacy with minimal adverse effects helps to quantify an appropriate RBV. High lung deposition/targeting, high receptor binding, longer pulmonary retention, and high lipid conjugation are among the pharmacokinetic parameters to be considered for improved efficacy of the compound. Low or negligible oral bioavailability, small particle size and inactive drug at the oropharynx, high plasma protein binding, rapid metabolism, high clearance, and lower systemic concentrations are associated with low risks for adverse effects. Inhaled glucocorticoid potency is enhanced by solution inhalers, which result in higher pulmonary deposition and minimize local adverse effects. These properties, among others, determine the efficacy and safety of inhaled glucocorticoids. Currently available inhaled glucocorticoids do not provide the complete pharmacokinetic/pharmacodynamic parameters to optimize RBV, leaving room for improvement in the development of future agents.
Research Interests: Asthma, Pharmacokinetics, Clinical Pharmacology, Risk assessment, Pharmaceutical Chemistry, and 13 moreHumans, The, Pharmacodynamics, Particle Size, Risk Assessment, Low Risk, Protein Binding, Biological Availability, Glucocorticoid Receptors, Glucocorticoids, Lung deposition, Adverse effect, and plasma proteins
Dipyridamole (DP) is an antiplatelet agent that shows decreased oral bioavailability with increased gastric pH that occurs with commonly prescribed antacids. An extended-release (ER) formulation of DP that employs tartaric acid to improve... more
Dipyridamole (DP) is an antiplatelet agent that shows decreased oral bioavailability with increased gastric pH that occurs with commonly prescribed antacids. An extended-release (ER) formulation of DP that employs tartaric acid to improve bioavailability of DP in the presence of elevated gastric pH was developed as a combination antiplatelet product with immediate-release aspirin. This crossover-designed study examined the relative bioavailability of DP from the composite product compared to conventional DP tablets during reduced gastric acidity. Gastric pH was increased (pH &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; 4.0) in 20 healthy subjects with lansoprazole (30 mg/d for 5 days). Dipyridamole systemic exposure over 12 hours was compared after oral administration of a single composite ER capsule (200 mg DP + 25 mg aspirin) versus two 100-mg conventional DP tablets given 6 hours apart combined with 81 mg aspirin. DP relative bioavailability was reduced 53% with conventional tablets compared to the composite buffered ER capsule in reduced gastric acid conditions. Peak DP plasma concentrations were 57% lower with immediate-release tablets compared to the composite formulation with high stomach pH. Substituting generic DP plus low-dose aspirin may be less effective than the buffered DP composite product in patients with concomitant antacid therapies.
Research Interests:
Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both... more
Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic groups. The International Conference on Harmonization (ICH) published a guidance to facilitate the registration of drugs among ICH regions (European Union, Japan, the United States) by recommending a framework for evaluating the impact of ethnic factors on a drug&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s effect, as well as its efficacy and safety at a particular dosage and dosage regimen. This review focuses on the pharmacokinetic differences between East Asians and Caucasians. Differences in metabolism between East Asians and Caucasians are common, especially in the activity of several phase I enzymes such as CYP2D6 and the CYP2C subfamily. Before drug therapy, identification of either the genotype and/or the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. Furthermore, these differences are relevant for international drug approval when regulatory agencies must decide if they accept results from clinical trials performed in other parts of the world.
Research Interests: Genetics, Clinical Trial, European Union, Pharmacokinetics, Clinical Pharmacology, and 14 moreHumans, Far East, United States, Enzyme, Ethnic Group, Genetic Polymorphism, Drug Therapy, European Continental Ancestry Group, Asian Continental Ancestry Group, Genetic variation, Medical Treatment, Pharmaceutical preparations, Adverse effect, and therapeutic index
Research Interests:
The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as... more
The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as placebo. Twenty-two different pharmacodynamic parameters were followed as a function of time for 48 hours. Statistically significant effects of the glucocorticoids were an increase in blood glucose levels, a decrease in the number of lymphocytes, eosinophils, basophils, and monocytes, and an increase in the number of granulocytes and stab cells. For the most significant pharmacodynamic effects (lymphocytes, granulocytes, and glucose) a previously derived integrated pharmacokinetic/pharmacodynamic model using plasma concentrations, protein-binding data, and in vitro receptor-binding affinities was used to predict the pharmacodynamic effect-time profiles. Good agreement of predicted and measured effects was observed, confirming the validity of the model. The clinical significance of the model was demonstrated by comparison of model-predicted maintenance doses with empirically determined clinical equivalency doses.