Genetic factors in drug metabolism.

Patients vary widely in their response to drugs. Having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is importantwhen assessing ethnic differences in drug response. Genetic factors can account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors) have been identified. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react differently to various drugs and to make better decisions about therapy. Ultimately, this understanding may shift the medical paradigm to highly individualized therapeutic regimens.

The use of wireless laptop computers for computer-assisted learning in pharmacokinetics.

OBJECTIVE: To implement computer-assisted learning workshops into pharmacokinetics courses in a doctor of pharmacy (PharmD) program. DESIGN: Workshops were designed for students to utilize computer software programs on laptop computers to build pharmacokinetic models to predict drug concentrations resulting from various dosage regimens. In addition, students were able to visualize through graphing programs how altering different parameters changed drug concentration-time curves. Surveys were conducted to measure students' attitudes toward computer technology before and after implementation. Finally, traditional examinations were used to evaluate student learning. ASSESSMENT: Doctor of pharmacy students responded favorably to the use of wireless laptop computers in problem-based pharmacokinetic workshops. Eighty-eight percent (n = 61/69) and 82% (n = 55/67) of PharmD students completed surveys before and after computer implementation, respectively. Prior to implementation, 95% of students agreed that computers would enhance learning in pharmacokinetics. After implementation, 98% of students strongly agreed (p < 0.05) that computers enhanced learning. Examination results were significantly higher after computer implementation (89% with computers vs. 84% without computers; p = 0.01). CONCLUSION: Implementation of wireless laptop computers in a pharmacokinetic course enabled students to construct their own pharmacokinetic models that could respond to changing parameters. Students had greater comprehension and were better able to interpret results and provide appropriate recommendations. Computer-assisted pharmacokinetic techniques can be powerful tools when making decisions about drug therapy.

Effect of pregnancy on the pharmacokinetics of paclitaxel: a case report.

Breast cancer during pregnancy is increasingly common as women delay childbearing until later in life. Safe administration of adjuvant chemotherapy during pregnancy has been reported. Physiologic and metabolic changes during pregnancy could alter the pharmacokinetics of these agents. This is a pilot study to prospectively study the pharmacokinetics of chemotherapeutic agents during pregnancy. Herein, we report the initial results with paclitaxel in the first patient.

Single-dose pharmacokinetics and tolerability of pegylated interferon-alpha2b in young and elderly healthy subjects.

AIMS: To assess the single-dose pharmacokinetics and tolerability of pegylated interferon-alpha2b (PEG-Intron) in young and elderly healthy subjects. METHODS: In this parallel-design study, a single 1 microg x kg(-1) PEG-Intron dose was given subcutaneously to 24 subjects in the age groups 20-45, 65-69, 70-74 and 75-80 years (n = 6/group). Blood sampling and tolerability assessments were performed up to 168 h postdose. RESULTS: The pharmacokinetic parameters were similar in all age groups. The elderly to young subject ratios for Cmax were 91.1, 79.5, and 107% for the 65-69 years, 70-74 years and 75-80 years groups, respectively. The corresponding values for AUC(0- infinity ) and CL/F were 111, 102 and 108%, and 82.5, 95.8 and 86.4%, respectively. Mean differences from the 20 to 45 years group and the 65-69 years, 70-74 years and 75-80 years groups for PEG-Intron Vd/F were 108, 128 and 104%, respectively. None of these differences was statistically significant based on ANOVA. Results from a Dunnett's test (as post hoc assessment) confirmed that the pharmacokinetic parameters of Group II, Group III or Group IV were not different from those of Group I. Almost all (23/24; 96%) subjects reported typical interferon-alpha side-effects (flu-like symptoms, headache). One elderly patient had a myocardial infarction 12 h postdose, but recovered fully. CONCLUSIONS: There are no pharmacokinetic reasons for initial dose adjustment of PEG-Intron based on age.

Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.

The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2 of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After coadministration with paroxetine, increases in N-desmethylatomoxetine and decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.

The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity.

AIMS: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. METHODS: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg(-1)) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral(50 microg ethinyloestradiol/500 microg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. RESULTS: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,infinity)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,infinity)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = -0.936). CONCLUSIONS: Administration of Ovral for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.