doi: 10.1016/0009-9236(95)90066-7pmid: 7628176
Clinical Pharmacology & Therapeutics (1995) 58, 1–14; doi: 10.1016/0009‐9236(95)90066‐7
Gomez, Denise Y.; Wacher, Vincent J.; Tomlanovich, Stephen J.; Hebert, Mary F.; Benet, Leslie Z.
doi: 10.1016/0009-9236(95)90067-5pmid: 7628178
The pharmacokinetics of cyclosporine were studied in the blood of five normal healthy volunteers (two men and three women) after each received oral and intravenous cyclosporine alone and with concomitant oral ketoconazole. Administration of ketoconazole caused a significant decrease in intravenous cyclosporine clearance (0.18 ± 0.05 L/kg/hr versus 0.32 ± 0.09 L/hr/kg) and a significant increase in cyclosporine oral bioavailability (56.4% ± 11.7% versus 22.4% ± 4.8%) compared with values before ketoconazole administration. Steady‐state volume of distribution for intravenously administered cyclosporine was unchanged (1.26 ± 0.44 L/kg versus 1.10 ± 0.27 L/kg). Hepatic bioavailability (1 — hepatic extraction ratio) calculated for intravenous cyclosporine increased by 11% in the presence of ketoconazole (86.3% ± 3.7% versus 75.2% ± 6.6% without ketoconazole), which accounts for only one third of the observed increase in cyclosporine oral bioavailability. Because it is unlikely that ketoconazole had a significant effect on either cyclosporine absorption or hepatic blood flow, the increase in cyclosporine bioavailability observed in this study is most likely explained by inhibition of gastrointestinal cytochrome P450 enzymes.
Straka, Robert J.; Hansen, Shawn R.; Walker, Patricia F.
doi: 10.1016/0009-9236(95)90069-1pmid: 7628180
Genetic polymorphism of the P450IID6 (CYP2D6) enzyme system can be an important component of the variability in response to drug therapy. Interpopulation differences in the prevalence of deficiencies of drug‐metabolizing enzymes may be clinically important in the selection and dosage of drug therapies for patients. Since 1980, the State of Minnesota has had more than a 1000% increase in population of Hmong refugees from Laos. The Hmong are frequently treated in our institution's international clinic with virtually no systematically acquired knowledge about the ability of this relatively ethnically pure population to metabolize commonly used Western medications. To further our knowledge of drug metabolism in this population, we identified the prevalence of the poor metabolizer phenotype for CYP2D6 in a sample population of Hmong subjects and compared this prevalence to that in a sample population of white subjects. Urine collected after ingestion of dextromethorphan in 237 healthy Hmong and 280 healthy white volunteers was analyzed by HPLC. Based on probit plots of the metabolic ratios (dextro‐methorphan/dextrorphan), 8.9% of Hmong subjects and 6.1% of white subjects were assigned the poor metabolizer phenotype (difference not significant). Weak associations were found between body surface area and metabolic ratio for both Hmong and white men and between smoking status and metabolic ratio for white subjects only. We conclude that the prevalence of poor metabolizers for the CYP2D6 enzyme system is similar between Hmong subjects and white subjects residing in Minnesota and that an antimode of 0.3 for metabolic ratio appears to be reasonable for the populations studied.
Mould, Diane R.; DeFeo, Tina Marie; Reele, Stots; Milla, Grace; Limjuco, Raul; Crews, Theodore; Choma, Nadia; Patel, Indravadan H.
doi: 10.1016/0009-9236(95)90070-5pmid: 7628181
The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four‐way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization (“learning curve”) with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma—effect site equilibrium half‐life was approximately 2½ times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.
Zhang, Ruiwen; Yan, Jieming; Shahinian, Harout; Amin, Girish; Lu, Zhihong; Liu, Tiepu; Saag, Michael S.; Jiang, Zhiwei; Temsamani, Jamal; Martin, R. Russell; Schechter, Paul J.; Agrawal, Sudhir; Diasio, Robert B.
Doenicke, Alfred; Moss, Jonathan; Lorenz, Wilfried; Hoernecke, Rainer
doi: 10.1016/0009-9236(95)90075-6pmid: 7543038
Patients receiving intravenous morphine at doses of 0.3 and 1.0 mg/kg for general anesthesia have been reported to show significant elevations in plasma histamine that are associated with hemodynamic changes. We undertook a prospective, randomized, double‐blind trial in which 0.15 mg/kg morphine or 0.3 mg/kg nalbuphine was administered intravenously to normal volunteers. Thirteen of 15 subjects receiving morphine and 10 of 14 subjects receiving nalbuphine had elevations in plasma histamine levels and symptoms of histamine release within 5 minutes of drug administration. Six subjects in the morphine group and five in the nalbuphine group exhibited levels of plasma histamine >2.0 ng/ml, but these levels were not associated with hemodynamic changes and occurred 10 to 15 minutes after drug administration. Our study suggests that the opiate‐induced elevation of plasma histamine derives from cutaneous mast cells.
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doi: 10.1016/0009-9236(95)90071-3pmid: 7628182
Human pharmacokinetics of an antisense oligodeoxynucleotide phosphorothioate (GEM 91) developed as an anti—human immunodeficiency virus (HIV) agent was carried out in this study. 35S‐Labeled GEM 91 was administered to six HIV‐infected individuals by means of 2‐hour intravenous infusions at a dose of 0.1 mg/kg. Plasma disappearance curves for GEM 91—derived radioactivity could be described by the sum of two exponentials, with half‐life values of 0.18 ± 0.04 and 26.71 ± 1.67 hours. The radioactivity in plasma was further evaluated by polyacrylamide gel electrophoresis, showing the presence of both intact GEM 91 and lower molecular weight metabolites. Urinary excretion represented the major pathway of elimination, with 49.15% ± 6.80% of the administered dose excreted within 24 hours and 70.37% ± 6.72% over 96 hours after dosing. The radioactivity in urine was associated with lower molecular weight metabolites. No drug‐related toxicity was observed.