Michael W. Jann

Effects of carbamazepine on plasma haloperidol levels

Plasma haloperidol levels were monitored in three schizophrenic patients when carbamazepine was either added or discontinued. The percent decrease in plasma haloperidol levels due to concomitant carbamazepine therapy was between 59% and 61%. The effects of carbamazepine on plasma haloperidol levels were noted to occur in 2 to 3 weeks. Although no adverse effects occurred in the patients during therapy, careful monitoring of clinical symptoms and plasma haloperidol levels is recommended.

Thiothixene pharmacokinetic interactions : a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.

Correlation of cytochrome P450 (CYP) 1A2 activity using caffeine phenotyping and olanzapine disposition in healthy volunteers.

Olanzapine has previously been shown to have predominant metabolism by cytochrome (CYP) P450 1A2. Caffeine has been shown to provide an accurate phenotypic probe for measuring CYP1A2 activity. The purpose of this study is to determine if a significant correlation exists between olanzapine disposition and caffeine metabolic ratios. Subjects were phenotyped for CYP1A2 activity with caffeine probe methodology. After 200-mg caffeine administration, blood (4 h), saliva (6 and 10 h), and urine (8 h total) were collected for high-performance liquid chromatography (HPLC) analysis of caffeine and its metabolites.CYP1A2 activity was measured as plasma (PMR4 h), saliva (SMR6 h and SMR10 h), and three urinary metabolic (UMR18 h, UMR28 h, and UMR38 h) ratios. Each of the 14 healthy nonsmokers (13 male) received a single 10 mg olanzapine dose after which blood was collected for HPLC determination of olanzapine concentrations at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, and 120 h postdose. Olanzapine pharmacokinetic parameters in this study were similar to those previously published. All caffeine metabolic ratios (PMR4 h, SMR6 h, SMR10 h, UMR18 h, and UMR28 h) significantly correlated with each other (p<0.001) except for UMR38 h, which did not correlate. A significant correlation (p<0.05) was also found between olanzapine clearance and PMR4 h (r=0.701), SMR6 h (r=0.644), SMR10 h (r=0.701), UMR18 h (r=0.745), and UMR28 h (r=0.710). A negative correlation was observed between olanzapine clearance and UMR38 h (r=−0.029, p=NS). A significant correlation was found between olanzapine clearance and various caffeine metabolic ratios. Interpatient variability in CYP1A2 activity may explain the wide interpatient variability in olanzapine disposition. Compounds that modulate CYP1A2 activity may be expected to alter olanzapine pharmacokinetics accordingly.

Clinical Pharmacists' Impact on Prescribing in an Acute Adult Psychiatric Facility

An analysis is presented of data collected to evaluate the impact of a clinical pharmacy service on an acute psychiatric admitting unit. Retrospective longitudinal drug utilization reviews (RLDUR) were performed one year apart (pre- and post-implementation of services) on the same treatment team. Process measures significantly affected include (percent reduction): total drugs/patient (33.9), number of antipsychotic drugs/patient (38.0), number of anticholinergics started on admission/patient (53.2), and number of doses/patient/d (42.4). Other drug-use parameters significantly affected include: a 42-percent increase in the mean dosage expressed as chlorpromazine equivalents, and a 47-percent reduction in the number of patients on low potency antipsychotic medications. Beneficial outcome was reflected by a faster rate of discharge or transfer to a less restrictive ward environment in the pharmacy study population. The study population also demonstrated a 55.8-percent decrease in their readmission rate to the facility over a one-year follow-up period. Clinical pharmacy services positively affect both process and outcome health care measures.

Applied Clinical Pharmacokinetics and Pharmacodynamics of Psychopharmacological Agents

Pharmacokinetics is the mathematical characterization of the time course of drug absorption, distribution, metabolism, and excretion. Over the past 50 years, dramatic scientifi c advances have revolutionized drug development and design and clinical decision making. These include improvements in quantitating drug and metabolite concentrations in biologic matrices (plasma and tissue), measuring drug effects, and understanding how genetics, metabolic pathways, and drug transporters infl uences drug disposition. A major challenge for health-care professionals in clinical psychopharmacology is in understanding and adjusting for individual differences in a drug’s response. Knowledge of a drug’s pharmacokinetic characteristics can be leveraged to help resolve these issues and formulate rational drug therapy decisions. As an example, understanding the absorption and distribution characteristics of a drug allows one to predict the amount of an administered dose that is expected to enter the bloodstream and reach its site of action. Further, an understanding of drug metabolism and elimination allows for the prediction of drug concentrations when it is administered on a repeated basis (i.e., under steady-state conditions); this allows for the rational selection of dosing regimens. Dose and regimen selection must also take drug interactions, genetic polymorphisms, comorbid conditions, and aging into account since all of these can impact drug exposure, effi cacy, and toxicity. M. S. Luer , PharmD, FCCP ( ) Department of Pharmacy Practice , Southern Illinois University Edwardsville School of Pharmacy , Campus Box 2000 , Edwardsville , IL 62026-2000 , USA e-mail: mluer@siue.edu S. R. Penzak , PharmD, FCP Department of Pharmacotherapy , University of North Texas, Health Sciences Center, System College of Pharmacy , 3500 Camp Bowie Blvd , Fort Worth , TX 76107 , USA e-mail: scott.penzak@unthsc.edu

Future Directions for Pharmacogenetics

The discipline of pharmacogenetics will continue to expand as scientific and clinical investigations increase our understanding of genetic variabilities in drug metabolism and response. These research efforts will include determination of molecular mechanisms for the different polymorphisms and evaluation of their clinical significance. The availability of molecular methodologies such as restriction fragment length polymorphisms analysis, polymerase chain reaction, and expression of cDNAs in cell cultures will further the investigative work in detection of normal and mutant alleles, identification of new substrates for different polymorphic metabolizing enzymes, and evaluation of mechanisms of individual susceptibility to biological disorders. Other areas such as the role of pharmacogenetics in drug development and regulatory control, in evaluation of potential drug-drug interactions, ethnic variation in polymorphic metabolism, and response, also need to be evaluated.