C. Lindsay DeVane

Pharmacokinetics of bupropion and its major basic metabolites in normal subjects after a single dose

The pharmacokinetics of bupropion (BUP) and its three major basic metabolites (the erythroamino alcohol [EB], the threoamino alcohol [TB], and the hydroxy [HB] metabolites) were characterized after a single, oral, 200 mg dose of BUP in six healthy men. Twenty‐one sequential plasma samples for analysis by HPLC were drawn from each subject over the 56‐hour period after dosing. Pharmacokinetic analyses were by noncompartmental methods. The mean elimination t½ values of BUP, TB, EB, and HB were 9.8, 19.8, 26.8, and 22.2 hours, respectively. The mean plasma AUCs of TB and HB were 2.4 and 10.3 times greater, respectively, than that for BUP. Because of the substantial presence of these metabolites in systemic circulation, further studies are recommended to understand further their roles in the clinical profile of this new antidepressant.

Influence of menstrual cycle and gender on alprazolam pharmacokinetics

The effects of menstrual cycle phases and gender on alprazolam pharmacokinetics were evaluated in normal volunteers. Alprazolam (1 mg) was administered to seven women during the late follicular and luteal phases of the menstrual cycle and to eight men on one occasion. No difference in alprazolam pharmacokinetic parameters was observed during the menstrual cycle phases. Mean alprazolam clearance (±SD) was 0.0037 ± 0.0009 ml/hr during the follicular phase and 0.0036 ± 0.001 ml/hr during the luteal phase (p > 0.05, difference not significant). With use of weight as a covariant, there was no difference in alprazolam pharmacokinetic parameters between women and men. Mean alprazolam clearance (±SD) was 0.0036 ± 0.0009 ml/hr in women compared with 0.0041 ± 0.0006 ml/hr in men (p > 0.05, difference not significant). Although alprazolam metabolism was similar on the 2 days tested, alterations may occur at other times during the menstrual cycle. Further investigation is needed to understand the effects of menstrual cycle phases and gender on drug metabolism.

Tissue distribution of cocaine in the pregnant rat

Cocaine hydrochloride was administered by single intraperitoneal (IP) doses to pregnant rats at day 18 or 19 of gestation. Plasma and tissue cocaine and norcocaine concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic analysis of concentration versus time data showed rapid distribution of cocaine and its metabolite to maternal and fetal tissues. The area under the cocaine concentration versus time curve (AUC) in fetus compared to maternal plasma was 3.33. The half-life of cocaine in the maternal plasma and fetus was 46 and 55 minutes, respectively, similar to values reported for cocaine elimination half-life in human plasma. The order of cocaine concentrations was placenta greater than fetal liver greater than maternal heart greater than whole fetus greater than fetal brain greater than maternal brain = maternal plasma. Norcocaine concentrations were usually less than 20% of cocaine concentrations in plasma and tissues. These results support extensive fetal exposure to cocaine following administration to pregnant rodents. Pharmacodynamic studies of cocaine in pregnancy should consider the effects of the drug on the developing fetus.

Posttraumatic stress disorder: Characteristics and pharmacological response in the veteran population

Abstract A retrospective chart review was conducted on all patients with the primary diagnosis of posttraumatic stress disorder (PTSD) admitted over a one-year period to a Veterans Administration Medical Center. The data base consisted of 14 Vietnam veterans and one World War II veteran. The purpose of the review was to compare the symptom profile of combat veterans to the established DSM III criteria for PTSD and to evaluate the efficacy of pharmacotherapy. The veterans symptomatology was much more complex than described in DSM III and the currently employed drug therapy appears to be generally inadequate in treating combat-related PTSD.

Clinical Implications of Antidepressant Pharmacokinetics and Pharmacogenetics

OBJECTIVE: To review available data on pharmacokinetic and pharmacogenetic influences on the response to antidepressant therapy, analyze the mechanisms for and clinical significance of pharmacokinetic and pharmacogenetic differences, and explain the implications of pharmacokinetics and pharmacogenetics for patient care. DATA SOURCES: A MEDLINE search of English-language clinical studies, abstracts, and review articles on antidepressant pharmacokinetics, pharmacogenetics, and drug interactions was used to identify pertinent literature. DATA SYNTHESIS: The pharmacokinetic profiles of selected antidepressants are reviewed and the impact of hepatic microsomal enzymes on antidepressant metabolism is considered. How phenotypic differences influence the metabolism of antidepressant drug therapy is addressed. To evaluate the clinical implications of these pharmacokinetic and pharmacogenetic considerations, the findings of studies designed to elucidate drug interactions involving antidepressant agents are discussed. CONCLUSIONS: Differences in antidepressant plasma concentrations, and possibly safety, are caused by polymorphism in the genes that encode some of the cytochrome P450 isoenzymes that metabolize antidepressants. The isoenzymes 1A2, 2C9/19, 2D6, and 3A4 are the major enzymes that catalyze antidepressant metabolic reactions. Antidepressants can be either substrates or inhibitors of these enzymes, which also metabolize many other pharmacologic agents. Although the cytochrome enzymes that metabolize antidepressants have not been fully characterized, interaction profiles of the newer antidepressants are becoming more clearly defined. Determining patient phenotypes is not practical in the clinical setting, but an awareness of the possibility of genetic polymorphism in antidepressant metabolism may help explain therapeutic failure or toxicity, help predict the likelihood of drug interactions, and help clinicians better manage antidepressant drug therapy.

Immunologic Effects of Cocaine and Related Alkaloids

Because of the national epidemic of cocaine abuse and the increasing prevalence of infectious diseases among drug abusers, we investigated the effects of cocaine and cocaine metabolites on human cellular immune functions. Mononuclear cells (MNC) were isolated from blood of healthy adult volunteers. MNC were stimulated in vitro with mitogens with and without various concentrations of cocaine. Because of cocaines poor stability in vitro, we found it necessary to replenish cocaine daily to MNC cultures. Under these conditions, cocaine, in a dose response fashion, significantly inhibited MNC proliferation. Metabolites of cocaine did not alter MNC proliferative responses significantly from control cultures. Polymorphonuclear leukocyte chemotaxis was also significantly impaired by cocaine. Our data demonstrate that cocaine is immunosuppressive and that it acts on human MNC during early stages of cellular activation. These data further suggest that illicit cocaine use may compromise the integrity of the immune system.

Evaluation of population pharmacokinetics in therapeutic trials. IV: Application to postmarketing surveillance

The feasibility of incorporating blood sampling for population pharmacokinetic analysis into postmarketing surveillance was evaluated. Demographic and drug disposition data, consisting of two blood samples collected at a random time during two different dose intervals, was prospectively collected for 94 psychiatric inpatients (mean age, 48 ± 13 years) receiving alprazolam. Mixed‐effect modeling was used to estimate population pharmacokinetic parameters. The mean alprazolam clearance, volume of distribution, and absorption rate constant were 0.05 L/hr/kg, 0.7 L/kg, and 1.1 hr−1 respectively. Clearance was increased by 59% in women, decreased by 26% in patients with multiple organ disease, and decreased by 23% in patients older than 60 years of age. These estimates are similar to those determined from rigorous premarketing clinical trials. Interindividual variability in alprazolam clearance was relatively small (40%) after adjustment for significant patient covariates. Population pharmacokinetic analysis represents a reasonable approach to assessment of pharmacokinetic variability in a large, heterogenous patient population.

Plasma Concentration Monitoring of Hydroxylated Metabolites of Imipramine and Desipramine

Steady-state serum concentrations of imipramine (IMI), its demethylated metabolite desipramine (DMI), and the active, hydroxylated metabolites, 2-hydroxy-imipramine (2-OH-IMI) and 2-hydroxy-desipramine (2-OH-DMI) were monitored in 126 psychiatric patients receiving IMI therapy. DMI and 2-OH-DMI concentrations were determined in a similar group of 61 DMI-treated patients. Although significant correlations exist between hydroxy metabolite and precursor concentrations, considerable variability was also found. Mean (± SD) ratios for the IMI patients were: 2-OH-IMI:IMI = 0.27 (± 0.19) and 2-OH-DMI:DMI = 0.56 (± 0.30). The ratio of DMI: IMI for males and 2-OH-DMI:DMI for females decreased with age (r = −0.42 and −0.32, respectively, p < 0.01). Variable metabolite concentrations and the uncertainty of their relative psychoactivity may contribute to the difficulties in relating antidepressant efficacy to serum concentrations of the administered IMI or DMI.

Hemoperfusion for Imipramine Overdose: Elimination of Active Metabolites

The serum concentrations of imipramine and its pharmacologically active metabolites were followed during resin hemoperfusion for imipramine overdose. The initial serum concentration of 2-hydroxy-imipramine plus 2-hydroxy-desipramine was 13.3% of the total tricyclic antidepressant level (imipramine + desipramine + hydroxymetabolites). Despite high extraction ratio (greater than or equal to 0.75) and clearances (130--180 mL/min) for both imipramine and its metabolites, the calculated amount of drug removed was small. Only 0.91% of the estimated dose ingested was removed as imipramine, 0.52% as desipramine, and 0.33% as hydroxylated metabolites. While the hydroxylated metabolites of imipramine may contribute to its toxicity, it is unlikely that the small amount removed can explain reports of apparent clinical benefit from hemoperfusion.

Determination of cocaine, benzoylecgonine and ecgonine methyl ester in plasma by reversed-phase high-performance liquid chromatography

A combined assay is described for cocaine and its major metabolites, benzoylecgonine and ecgonine methyl ester. The method uses electrochemical and ultraviolet detectors in series. A non-silica column is used with high-pH mobile phase. The three compounds are completely separated from other cocaine metabolites. The assay has been suitable for pharmacokinetic studies of cocaine disposition in animal studies.