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To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3beta-acetoxyandrost-5-ene-7,17-dione) given orally. A randomized, double blind, placebo-controlled, escalating dose study. The Chicago Center for Clinical Research.... more
To evaluate the safety and pharmacokinetics of 3-acetyl-7-oxo-DHEA (3beta-acetoxyandrost-5-ene-7,17-dione) given orally. A randomized, double blind, placebo-controlled, escalating dose study. The Chicago Center for Clinical Research. Twenty-two healthy men. The participants received placebo (n = 6) or 3-acetyl-7-oxo-DHEA (n = 16) at 50 mg/d for 7 days followed by a 7-day washout; 100 mg/d for 7 days followed by a 7-day washout; and 200 mg/d for 28 days. Safety parameters, evaluated at each dose level, included measurement of total testosterone, free testosterone, dihydrotestosterone, estradiol, cortisol, thyroxin and insulin levels. Analyses for 7-oxo-DHEA-3beta-sulfate (DHEA-S), the only detectable metabolic product of the administered steroid, were conducted on plasma drawn from all subjects at 0.25, 0.5, 1, 2, 4, 6 and 12 hours after the final 100 mg dose of 3beta-acetyl-7-oxo-DHEA. There were no differences in the clinical laboratory values or in reported minor adverse experiences, between treatment and placebo groups. In general, blood hormone concentrations were unaffected by the treatment with 3beta-acetyl-7-oxo-DHEA and remained within the normal range. No changes in vital signs, blood chemistry or urinalysis occurred during treatment with 3beta-acetyl-7-oxo-DHEA compared to placebo. The administered steroid was not detected in the blood but was rapidly converted to 7-oxo-DHEA-S, the concentrations of which were proportional to dose. This steroid sulfate did not accumulate; plasma concentrations 12 hours after the 3beta-acetyl-7-oxo-DHEA dose at 7 and 28 days on the 200 mg/d dose were 15.8 and 16.3 microg/L respectively. The mean time to peak plasma level of 7-oxo-DHEA-S was 2.2 hours; the mean half life was 2.17 hours. The apparent clearance averaged 172 L/h, and the apparent mean volume of distribution was 540 L. These results indicate that 3beta-acetyl-7-oxo-DHEA is safe and well tolerated in normal healthy men at doses up to 200 mg/d for 4 weeks.
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Research Interests:
Linking biomarker data to pharmacokinetic (PK) models permits comparison of absorbed dose with a toxicological benchmark, which is an important step to understanding the health implications of pesticide exposure. The purpose of this... more
Linking biomarker data to pharmacokinetic (PK) models permits comparison of absorbed dose with a toxicological benchmark, which is an important step to understanding the health implications of pesticide exposure. The purpose of this analysis was to evaluate the feasibility of reconstructing the absorbed dose of two pesticides using PK models developed from biomarker data in a study of occupational application of these compounds. Twenty-four-hour urine samples were collected from farmers 24 h before through 96 h after a typical application of chlorpyrifos or 2,4-D. PK models were used to link the amounts found in urine samples to absorbed dose. Modeled total body dose estimates (in micrograms) were compared to measured dose from time 0-96 h. Despite the complexities surrounding the interpretation of biomonitoring data from a field setting, the models developed as part of this analysis accurately estimated the absorbed dose of 2,4-D and chlorpyrifos when collection of urine samples was largely complete. Over half of the farmers were excluded from modeling due to suspected noncompliance with urine collection or confounding exposure events, which highlights the importance of these issues for designing and interpreting biomonitoring data in future studies. Further evaluation of PK models in scenarios using single void samples is warranted for improving field-based dose assessments.
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We describe a liquid-chromatographic assay for phenytoin and its para-hydroxylated metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, in plasma and urine. Unlike previously reported methods, this procedure is sensitive enough to allow... more
We describe a liquid-chromatographic assay for phenytoin and its para-hydroxylated metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin, in plasma and urine. Unlike previously reported methods, this procedure is sensitive enough to allow quantitation of the unconjugated metabolite in plasma at concentrations observed clinically (50-500 microgram/L). Simultaneous measurements of the drug and its metabolite in plasma and urine may be helpful in explaining changes in the apparent clearance of phenytoin, assumed to occur through its metabolite. The method may also be used, without modification, for analysis for phenobarbital and carbamazepine in plasma. The accuracy of our method for these three drugs was assessed for 25 months in quality-assurance program for determining drug concentrations. Regression slopes for measured vs reported values for phenytoin, phenobarbital, and carbamazepine were 1.02, 0.99, and 0.99, respectively.
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This study evaluated the effect of a standard meal on the multiple-peak behavior of diclofenac sodium following oral administration of a 100-mg slow-release (SR) wax-matrix tablet. The study was a randomized, 3 × 3 Latin-square trial... more
This study evaluated the effect of a standard meal on the multiple-peak behavior of diclofenac sodium following oral administration of a 100-mg slow-release (SR) wax-matrix tablet. The study was a randomized, 3 × 3 Latin-square trial balanced for residual effects, in which 18 subjects were randomly assigned to treatment sequences consisting of three treatments: (A) one 100-mg SR tablet, fasted; (B) one 100-mg SR tablet, fed; and (C) 100-mg diclofenac sodium buffered aqueous solution, fasted. Blood samples were obtained over a 24-h period for Treatments A and B, and over an 8-h period for Treatment C. Food did not significantly affect the extent of absorption but generally delayed the onset of absorption from the SR tablet. The plasma concentration-time profile for the SR tablet under fasted conditions was characterized by multiple-peak behavior. Under fed conditions, the SR tablet showed a more consistent absorption pattern, with a single peak occurring usually between 5 and 6 h. The concentration-time profile of the buffered aqueous solution showed a very rapid absorption phase followed by a rapid decline and a terminal elimination half-life of approximately 1.8 h. A single peak was observed following the buffered aqueous solution. This observation, in conjunction with evidence from other studies, leads to the conclusion that gastrointestinal pH may be responsible for the multiple-peak behavior observed following diclofenac sodium dosing. As compared to the solution, the was-matrix tablet under both fasted and fed conditions showed slow-release, characteristics.
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The intestinal permeability of carbamazepine, an antiepileptic drug, was examined as a function of intestinal site (duodenojejunum vs colon). A "through-and-through" in situ intestinal perfusion technique... more
The intestinal permeability of carbamazepine, an antiepileptic drug, was examined as a function of intestinal site (duodenojejunum vs colon). A "through-and-through" in situ intestinal perfusion technique was adopted using the rabbit as an animal model. Coperfusion of the 10,11-epoxide and the 10,11-transdihydrodiol metabolites along with carbamazepine allowed for an examination of the effect of lipophilicity on intestinal permeability when molecular weight differences are negligible. Our results showed that carbamazepine is absorbed from rabbit duodenojejunum as well as the colon, which may explain the prolonged absorption behavior observed in humans. Also, the absorptive clearance of compounds having similar molecular weights is dependent not only on the lipophilicity but also on the extent of solvent drag during the course of the perfusion.
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A patient with chronic renal failure did not respond to "therapeutic" serum phenytoin concentrations as measured by enzyme-multiplied immunoassay (EMIT). Her seizure disorder was not controlled despite phenytoin... more
A patient with chronic renal failure did not respond to "therapeutic" serum phenytoin concentrations as measured by enzyme-multiplied immunoassay (EMIT). Her seizure disorder was not controlled despite phenytoin concentrations of 25-35 micrograms/ml. When her serum samples were reassayed by high pressure liquid chromatography and gas-liquid chromatography, the phenytoin serum concentrations were found to be approximately 1/2 of the previously reported values, that is, 16.0 micrograms/ml vs. 33 micrograms/ml. The precise reason for this discrepancy is currently unknown. Our findings suggest that the EMIT assay may yield falsely elevated serum phenytoin concentrations in uremic subjects.
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The pharmacokinetic consequences of alterations in the blood plasma distribution of cyclosporine are examined in this study. A series of solutions of cyclosporine of known concentration were prepared in rabbit blood. The plasma, separated... more
The pharmacokinetic consequences of alterations in the blood plasma distribution of cyclosporine are examined in this study. A series of solutions of cyclosporine of known concentration were prepared in rabbit blood. The plasma, separated at 37 degrees C, was then assayed for cyclosporine using an HPLC method. A mathematical model relating the blood and plasma concentrations of cyclosporine at equilibrium was derived and used to fit the data. The model assumes that the free fraction of the drug in plasma (fp) is constant but that the free fraction in blood is not. In the rabbit, fp was estimated to equal 0.405. This may be attributed to cyclosporine binding to lipoproteins, and to the lower concentrations of lipoproteins in rabbit serum compared to that in human serum. The capacity factor and the binding affinity constant of the drug for blood cells were estimated to equal 3590 micrograms/liter and 0.00682 liter/microgram in the rabbit. These results and the findings of a previous study suggest that the free fraction of the drug in blood increased, while the free intrinsic clearance did not change, with increases in the steady state blood concentration of the drug. It was concluded that the changes in binding characteristics of cyclosporine in blood at higher concentration and not the changes in the metabolic activity of the liver, as measured by intrinsic clearance, are responsible for the nonlinear pharmacokinetic behavior exhibited by cyclosporine in the rabbit.
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A two-part study was conducted to characterize the pharmacokinetics of cyclosporine in rabbits. First, cyclosporine was given iv as boluses to nine rabbits in doses of 5, 10, and 20 mg/kg. At each dose level, three rabbits were used.... more
A two-part study was conducted to characterize the pharmacokinetics of cyclosporine in rabbits. First, cyclosporine was given iv as boluses to nine rabbits in doses of 5, 10, and 20 mg/kg. At each dose level, three rabbits were used. Analysis of blood samples collected was performed by HPLC. The data indicate an increase in the half-life of the terminal phase (255 to 550 min), and in the volume of distribution at steady state (3.16 to 7.82 liters/kg) with increasing dose (5 to 20 mg/kg). Cyclosporine was then administered to three rabbits by constant rate iv infusion. The infusion rate was altered to provide three different steady states within 36 hr in each animal. Infusion rates in two rabbits were increased from 16.8 to 65.4 micrograms/min, and in the third rabbit they were decreased from 65.4 to 16.8 micrograms/min. Blood samples were collected during and postinfusion. Doubling the infusion rate within each animal produced less than double the steady state concentration. All three rabbits showed the same trend. Thus, the total body clearance of cyclosporine increased with increasing infusion rate, indicating nonlinear pharmacokinetic behavior of cyclosporine in rabbits.
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To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. In the first part of... more
To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. 6 healthy, reproductively intact female Beagles, 4.9 to 5.2 years old, and weighing 9.5 to 11.5 kg. In the first part of the study, allopurinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the second part of the study, allopurinol was administered orally at a dosage of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was then reversed. In the third part of the study, allopurinol was administered IV (10 mg/kg), orally (15 mg/kg) with food, and orally (15 mg/kg) without food. Plasma samples were obtained at timed intervals, and concentrations of allopurinol and oxypurinol were determined. Maximal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when dogs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were significantly greater when dogs received 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allopurinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administration with food. A dose threshold exists beyond which additional allopurinol would not substantially further inhibit xanthine oxidase activity. Oral administration of > 15 mg of allopurinol/kg to dogs would not be expected to result in greater reduction of plasma and urine uric acid concentrations. Also, allopurinol may be administered to dogs for dissolution or prevention of urate uroliths without regard to time of feeding.
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We describe a liquid-chromatographic assay for AZT in human plasma and urine. This assay involves the use of two internal standards, allowing reference of AZT peaks to the appropriate internal standard, the choice depending on the range... more
We describe a liquid-chromatographic assay for AZT in human plasma and urine. This assay involves the use of two internal standards, allowing reference of AZT peaks to the appropriate internal standard, the choice depending on the range of concentrations encountered. This method is isocratic, specific, sensitive enough to allow quantification of AZT in concentrations observed clinically, and requires only 13 min of chromatographic time. We saw no interference from various over-the-counter and prescription drugs often used in treating the infectious complications of AIDS.
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Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of... more
Our objective was to describe the pharmacokinetics of meropenem in the peritoneal fluid (PF) of six patients with severe peritonitis and septic shock and to relate measured concentrations to the minimum inhibitory concentration of bacteria. Microdialysis catheters were placed into the peritoneal space during surgery. Meropenem concentrations in plasma and in PF were analyzed using compartmental modeling. Meropenem areas under the concentration-time curve were lower in PF than in plasma (average ratio, 73.8+/-15%) because of degradation confirmed ex vivo. Compartment modeling with elimination from a peripheral compartment described the data adequately, and was used to simulate steady-state concentration profiles in plasma and PF during various dosing regimens. At the currently recommended dosing regimen of 1 g infused over 20 min every 8 h, PF concentrations of meropenem in patients with severe peritonitis associated with septic shock reach values sufficient for antibacterial effects...
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To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. Microdialysis with on-line HPLC analysis was... more
To study the extent and time course of distribution of stavudine (d4T) into the central nervous system (CNS) and to investigate the transport mechanisms of antiviral nucleosides in the CNS. Microdialysis with on-line HPLC analysis was used to measure drug concentrations in the brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) in the freely-moving rat. The in vivo recovery of d4T and zidovudine (AZT) was estimated by retrodialysis, which was validated by the zero-net flux method. The CNS distribution of d4T was investigated during iv and intracerebroventricular (icv) infusion. In the subsequent studies, the effect of AZT on CNS distribution of d4T was examined. During iv infusion, d4T distributed rapidly into the CNS. Its brain ECF/plasma and CSF/plasma steady-state concentration ratios were 0.33 +/- 0.06 and 0.49 +/- 0.12, respectively (n = 15). During icv infusion, the steady-state d4T concentrations in the brain ECF were 23-fold higher than those during iv infusion, wh...
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Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active... more
Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite, and low concentrations are associated with rejection after organ transplantation. We hypothesized that low MPA was associated with poorer engraftment and a higher incidence of acute graft versus host disease. We evaluated the pharmacokinetics in 87 adult subjects undergoing nonmyeloablative-related and nonmyeloablative-unrelated hematopoietic cell transplantation who were receiving 1 g mycophenolate mofetil orally or intravenously every 12 hours plus cyclosporine (INN, ciclosporin). Subjects with an unbound MPA area under the curve (AUC) from 0 to 6 hours of less than 150 ng . h/mL had a higher cumulative incidence of grade II-IV acute graft versus host disease than subjects with a greater AUC (68% versus 40%, P = .02). An unbound AUC from 0 to...
Research Interests: Treatment Outcome, Clinical Pharmacology, Therapeutic drug monitoring, Humans, Cord Blood, and 18 moreFemale, Organ Transplantation, Male, Cyclosporine, High Pressure Liquid Chromatography, Aged, Middle Aged, Neutrophils, Adult, Area Under the Curve, Area Under Curve, Liver function tests, Graft-Versus-Host Disease, Cumulative Incidence, Mycophenolate mofetil, Hematopoietic Cell Transplantation, Hematopoietic Stem Cell Transplantation, and Immunosuppressive Agents
The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining... more
The objective of this review is to survey the recent literature regarding the various applications of microdialysis in pharmacokinetics. Microdialysis is a relatively new technique for sampling tissue extracellular fluid that is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses various aspects of the technique with regard to its use in pharmacokinetic studies, such as: quantitation of the microdialysis probe relative recovery, interfacing the sampling technique with analytical instrumentation, and consideration of repeated procedures using the microdialysis probe. The remainder of the review is devoted to a survey of the recent literature concerning pharmacokinetic studies that apply the microdialysis sampling technique. While the majority of the pharmacokinetic studies that have utilized microdialysis have been done in the central nervous system, a growing number of applications are be...
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Research Interests:
A retrodialysis (RD) method for the real-time calibration of on-line microdialysis (MD) procedures was investigated in vitro and in vivo. Calibration by retrodialysis was simultaneously validated through the use of a zero-net flux (ZNF)... more
A retrodialysis (RD) method for the real-time calibration of on-line microdialysis (MD) procedures was investigated in vitro and in vivo. Calibration by retrodialysis was simultaneously validated through the use of a zero-net flux (ZNF) method, which assumes directional independence of diffusion of the solute. In RD, a calibrator with dialysance (PeA; effective permeability-surface area product) similar to that of the compound of interest is introduced into the perfusate. If the calibrator is suitable, its loss from the perfusate during RD is identical to the recovery of the solute of interest determined simultaneously by normal MD. Two antiviral nucleosides (AZT and AZdU) which differ structurally by only a methylene group were utilized as solute and calibrator, respectively. Both nucleosides exhibited similar recovery and loss at flow rates of 0.5 to 5 microL/min in vitro, indicating a similar PeA product in this flow domain. Furthermore, both compounds showed similar loss into th...
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The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs... more
The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 +/- 17 vs 252 +/- 54 mL/hr/kg). The plasma levels of the metabolites 4'-hydroxy, 5-hydroxy, 3'-hydroxy, 4',5-dihydroxy, and 3'-hydroxy-4'-methoxy diclofenac were considerably lower in minipigs than in man after both i.v. and oral administration. These results suggest slower metabo...
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The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with... more
The synovial mean transit time of diclofenac was determined by two methods from existing plasma and synovial fluid concentration-time data. These data were obtained from single- and multiple-dosing regimens of diclofenac in patients with osteoarthritis and rheumatoid arthritis. Plasma and synovial fluid concentration-time data taken from the literature for four other nonsteroidal antiinflammatory drugs (etodolac, ibuprofen, indomethacin, and tenoxicam) were also analyzed. The two methods of data analysis rely on the determination of the ratio of the area under the synovial fluid concentration-time curve to the area under the plasma concentration-time curve. Both methods can be considered noncompartmental because in determining the first-order exit rate constant for the synovial fluid (the inverse of the synovial mean transit time), an analysis of the overall distribution and elimination characteristics of the drug is unnecessary. Method 1 makes use of the information contained in th...
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A freely moving rat model was developed to study the CNS distribution of EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of... more
A freely moving rat model was developed to study the CNS distribution of EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid). Microdialysis (MD) in the frontal cortex (FrC) and in the lateral ventricle (LV) of the rat brain was performed to measure the levels of EAB 515 in the cortical extracellular fluid (ECF) as well as in the cerebrospinal fluid (CSF). The femoral artery and femoral vein were cannulated for serial blood sampling and intravenous (i.v.) drug administration, respectively. EAB 515 was also administered via the intracerebroventricular (icv) route in a cross-over experiment. The in vivo recovery of EAB 515 across the MD probes was determined by simultaneous retrodialysis (RD) performed using a hydroxylated analog of EAB 515, as the RD calibrator (RDC). An extremely sensitive and selective on-line HPLC system with native fluorescence detection was developed for the simultaneous analysis of EAB 515 and RDC in microdialysate samples from rat CSF ...
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An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3'-hydroxydiclofenac, 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxy-4'-methoxydiclofenac) in human urine is described.... more
An HPLC method for the determination of diclofenac (DCF) and four of its metabolites (3'-hydroxydiclofenac, 4'-hydroxydiclofenac, 5-hydroxydiclofenac, and 3'-hydroxy-4'-methoxydiclofenac) in human urine is described. Following base hydrolysis, the samples were neutralized and extracted. Evaporated extracts were reconstituted in mobile phase containing ascorbic acid, and chromatographed, using flow-rate programming, on a reversed-phase column. Absolute recovery (average), was at least 78% for diclofenac and ranged from 75 to 85% for the four metabolites. Standard curves showed linearity over the range of concentrations of 0.2 to 40 ug/mL, using 0.25 mL of urine. Specificity was demonstrated by examining chromatograms of extracts of blank urine from 8 volunteers and 24 study subjects. Good accuracy was observed for all compounds over the concentration range of 0.2 to 40 ug/mL using 0.25 mL of urine. Based on accuracy and precision criteria, the limit of quantitation fo...
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The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a... more
The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a balanced crossover study. Administration of 500 mg probenecid every 6 hr prior to and during AZT dosing resulted in an increase in the average AUCAZT from 89 micrograms.min/ml (control) to 191 micrograms.min/ml during probenecid treatment. This was manifested by a corresponding decrease in CLTOT/F, which is attributed to the inhibitory effect of probenecid on the glucuronidation and renal excretion of AZT. Average CLR and CLTOT/F of AZT decreased from 4.76 and 28.7 to 2.98 and 14.1 ml/min/kg during control and probenecid treatment, respectively. AZT glucuronidation was affected to a greater extent than its renal excretion, as reflected by the decreased ratio of GAZT/AZT urinary recoveries. The terminal half-life of AZT was slightly longer during pr...
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A mean decrease in plasma phenytoin concentrations of 11-14% (p less than 0.005) was observed in seven patients within 4 days after influenza vaccination. Possible mechanisms are discussed.
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The kinetics of zidovudine (AZT) distribution into rabbit cerebrospinal fluid (CSF) were studied during continuous infusion of AZT and after iv bolus administration. The CSF/plasma steady-state AZT concentration ratio was 0.192 +/- 0.003.... more
The kinetics of zidovudine (AZT) distribution into rabbit cerebrospinal fluid (CSF) were studied during continuous infusion of AZT and after iv bolus administration. The CSF/plasma steady-state AZT concentration ratio was 0.192 +/- 0.003. That this ratio is less than unity, and the clearance from the CSF due to bulk flow is much smaller than the total CSF-to-plasma clearance, suggests active CSF-to-plasma transport of AZT. Probenecid coadministration significantly enhances AZT distribution into CSF when plasma and CSF concentrations of AZT are at steady state during continuous infusion of AZT or at a transient steady state after a single iv bolus dose administration. A linear pharmacokinetic model which describes the distribution of AZT into CSF and relates intercompartmental clearances between CSF and plasma was developed and was used to analyze the results. This analysis showed that probenecid enhances the distribution of AZT into the CSF by its effect on clearances between plasma...
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A liquid-chromatographic assay for the analysis of ganciclovir in plasma and urine is described. This assay involves the use of acyclovir, an antiviral drug structurally related to ganciclovir, as the internal standard. A two-step sample... more
A liquid-chromatographic assay for the analysis of ganciclovir in plasma and urine is described. This assay involves the use of acyclovir, an antiviral drug structurally related to ganciclovir, as the internal standard. A two-step sample preparation method is used. After protein is precipitated with acetonitrile and the addition of diethyl ether, ganciclovir and the internal standard are back extracted into a small volume of aqueous ammonium phosphate, taking advantage of their relatively high water solubility. This isocratic method is specific and sufficiently sensitive to allow quantification of ganciclovir throughout the entire range of concentrations observed during therapeutic use of this antiviral drug. There was no interference from various over-the-counter and prescription drugs often prescribed to patients most likely to receive ganciclovir therapy. This assay was used to analyze plasma and urine samples obtained after intravenous administration of ganciclovir to rabbits. B...
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... Analytical Procedure Lillian E. Riad,1 Keith K. Chan,2 and Ronald J. Sawchuk3 Received July 17, 1990; accepted November 2, 1990 KEY ... and elimination clearances for CBZE and CBZD, the clearance of CBZ through the epoxide pathway... more
... Analytical Procedure Lillian E. Riad,1 Keith K. Chan,2 and Ronald J. Sawchuk3 Received July 17, 1990; accepted November 2, 1990 KEY ... and elimination clearances for CBZE and CBZD, the clearance of CBZ through the epoxide pathway (fmCl) is isolated from the sum of all ...
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Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous... more
Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous solutions in rabbit intestinal permeability of carbamazepine in the duodenojejunum and the ascending colon using an in situ perfusion technique. In both segments the intestinal permeability varied inversely with the percentage of PEG-400, when the concentration of carbamazepine in the perfusing solution was maintained constant. The decreased permeability may be explained by a reduction in the thermodynamic activity of carbamazepine with increased concentrations of PEG-400, as well as by reverse solvent drag because of the hyperosmolarity of the perfusing solutions.
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The distribution of zidovudine (3'-azido-3'-deoxythymidine; AZT) into two regions of rabbit brain was investigated in crossover using microdialysis. Six rabbits had guide cannulas surgically implanted in the lateral ventricle and... more
The distribution of zidovudine (3'-azido-3'-deoxythymidine; AZT) into two regions of rabbit brain was investigated in crossover using microdialysis. Six rabbits had guide cannulas surgically implanted in the lateral ventricle and thalamus by stereotaxic placement. After recovery, microdialysis probes were positioned and i.v. bolus doses of 5, 10, 20, and 30 mg/kg were administered to each animal over a period of 2 weeks. Blood was drawn via a marginal ear vein catheter for 8 hr. Brain dialysate was collected at 3 microliters/min from ventricle and thalamus dialysis probes every 10 min. Simulated cerebrospinal fluid (CSF), to which 3'-azido-2',3'-dideoxyuridine (AZdU) was added, was used as perfusate. AZdU loss, which was measured during simultaneous retrodialysis, served as a marker for in vivo recovery of AZT. AZT concentrations in plasma, as well as in ventricle and thalamus dialysate, were determined using a sensitive HPLC assay, and AZdU was simultaneously an...
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The pharmacokinetics of zidovudine in the rabbit were studied during coadministration of probenecid at two infusion rates. Each animal (n = 6) served as its own control during an initial 8-hr infusion of zidovudine. In the second 8-hr... more
The pharmacokinetics of zidovudine in the rabbit were studied during coadministration of probenecid at two infusion rates. Each animal (n = 6) served as its own control during an initial 8-hr infusion of zidovudine. In the second 8-hr infusion period, probenecid was coadministered with zidovudine. Urine samples were collected by bladder flush hourly for 19 hr. Plasma samples were taken at the midpoint of the urine collection interval and at predetermined intervals for 3 hr postinfusion. Plasma concentrations of zidovudine reached steady state during control periods but showed incomplete attainment of steady state during the infusions of probenecid at the higher rate. Total and renal clearance of zidovudine were reduced by 24.0 +/- 4.0 and 20.7 +/- 15%, respectively, during low-dose probenecid treatment and 48.9 +/- 7.4 and 55.7 +/- 3.4%, respectively, with high-dose probenecid treatment. Plasma probenecid concentrations during low-dose and high-dose infusion were 56.9 +/- 12 and 248...
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ABSTRACT
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The pharmacokinetics of the antiviral drug 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis.... more
The pharmacokinetics of the antiviral drug 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl]guanine (DHPG) were examined in six patients receiving 2.5 or 5.0 mg/kg every 8 or 12 hours for human cytomegalovirus (HCMV) pneumonitis or retinitis. Biexponential decay with a mean distribution t1/2 of 0.23 hours and terminal t1/2 of 2.53 hours was observed. Total clearance correlated well with and exceeded creatinine clearance by a factor of 2.4. Mean volume of the central compartment was 15.26 L/1.73 m2 and the volume of distribution at steady state was 32.8 L/1.73 m2. Peak (model predicted) and trough plasma concentrations were 4.75 to 6.20 micrograms/ml and less than 0.25 to 0.63 microgram/ml, respectively, in patients receiving 2.5 mg/kg. Peak concentrations are well above those needed to inhibit HCMV at the 50% level (ID50) and troughs are near this ID50. Cerebrospinal fluid concentrations of DHPG indicate a penetration of 24% to 67%. No accumulation of DHPG was apparent in these patients. However, dosage reduction is necessary in renal insufficiency. Neutropenia occurred in one patient. The plasma concentration profile of DHPG suggests potential beneficial activity against HCMV.
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ABSTRACT
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ABSTRACT We studied the pharmacokinetics of valproic acid (VPA) in 37 children who were taking other antiepileptic drugs. Thirteen children were studied both after initial and while on maintenance valproic acid therapy. Significant... more
ABSTRACT We studied the pharmacokinetics of valproic acid (VPA) in 37 children who were taking other antiepileptic drugs. Thirteen children were studied both after initial and while on maintenance valproic acid therapy. Significant differences occurred between initial and maintenance therapy in the mean apparent volume of distribution and in apparent VPA clearance, whereas VPA half-life remained relatively constant. Analysis of data in the 13 children studied on two occasions demonstrated wide intrapatient variability of VPA pharmacokinetics. Children taking VPA together with other antiepileptic medications generally require higher doses of VPA given more frequently.
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In 14 burn patients treated for serious Gram-negative infections, the use of the previously recommended gentamicin dose of 5 mg/kg/day was found to result in subtherapeutic serum concentrations (peak concentration less than 4 mg/L). The... more
In 14 burn patients treated for serious Gram-negative infections, the use of the previously recommended gentamicin dose of 5 mg/kg/day was found to result in subtherapeutic serum concentrations (peak concentration less than 4 mg/L). The gentamicin half-life was found to be unusually short especially in the younger burn patients. Because of this shorter half-life the dosage interval was decreased to 4 hours to prevent extended periods of subtherapeutic serum concentrations. In addition, the daily dose of gentamicin was increased to achieve therapeutic peak concentration. Individualizing each patient's gentamicin regimen was thought to be instrumental in the favorable response of two patients with Pseudomonas ecthyma gangrenosum. The results of this study would strongly support the measurement of serum gentamicin levels in all burn patients with life-threatening infection. The gentamicin dosage regimen should then be individualized for each patient to provide optimal peak concentrations. In addition, patients demonstrating a short drug half-life may require a decreased dosage interval to prevent prolonged periods of sub-therapeutic concentrations.
Research Interests: Nursing, Adolescent, Humans, Child, Infant, and 7 moreClinical Sciences, Shell Half-Life, Middle Aged, Burns, Adult, Gentamicins, and Child preschool
Linking biomarker data to pharmacokinetic (PK) models permits comparison of absorbed dose with a toxicological benchmark, which is an important step to understanding the health implications of pesticide exposure. The purpose of this... more
Linking biomarker data to pharmacokinetic (PK) models permits comparison of absorbed dose with a toxicological benchmark, which is an important step to understanding the health implications of pesticide exposure. The purpose of this analysis was to evaluate the feasibility of reconstructing the absorbed dose of two pesticides using PK models developed from biomarker data in a study of occupational application of these compounds. Twenty-four-hour urine samples were collected from farmers 24 h before through 96 h after a typical application of chlorpyrifos or 2,4-D. PK models were used to link the amounts found in urine samples to absorbed dose. Modeled total body dose estimates (in micrograms) were compared to measured dose from time 0-96 h. Despite the complexities surrounding the interpretation of biomonitoring data from a field setting, the models developed as part of this analysis accurately estimated the absorbed dose of 2,4-D and chlorpyrifos when collection of urine samples was largely complete. Over half of the farmers were excluded from modeling due to suspected noncompliance with urine collection or confounding exposure events, which highlights the importance of these issues for designing and interpreting biomonitoring data in future studies. Further evaluation of PK models in scenarios using single void samples is warranted for improving field-based dose assessments.