Journal of Clinical Pharmacy and Therapeutics (1997) 22, 221–226 The effect of paroxetine on thiothixene pharmacokinetics S. K. Guthrie PharmD*†, M. Hariharan PhD†, A. A. Kumar*, G. Bader MD† and R. Tandon MD† *College of Pharmacy, The University of Michigan, and †Department of Psychiatry, The University of Michigan Medical School, Ann Arbor, MI 48109, U.S.A. SUMMARY Objective: In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. Method: Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre- treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 ml blood samples were collected over the next 72 h. Results: None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. Discussion: It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thio- thixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance. INTRODUCTION Since their marketing in the late 1980s, it has become apparent that the serotonin specific re-uptake inhibitors (SSRIs) can interfere with the oxidative metabolism of many drugs that are biotransformed via the cytochrome P450 (CYP450) enzymes. While full profiles of enzymatic inhibition have not yet been defined for all the SSRIs, such information has been partially delineated. For instance, it is known that fluoxetine and norfluoxetine are potent inhibitors of CYP2D6 (1, 2), mild to moderate inhibitors of CYP3A3/4 (3, 4), and they also possibly cause some inhibition of CYP2C (5) isoenzymes. Fluvoxamine is a potent inhibitor of CYP1A2 (6, 7), a mild to moderate inhibitor of CYP3A3/4 (4, 8), but causes only minimal inhibition of CYP2D6 (9). Sertraline causes mild to moderate inhibition of CYP2D6 (10) and CYP3A3 /4 (11). Paroxetine appears to exhibit rather selective and potent inhibition of CYP2D6 (4, 12, 13). It is generally assumed that most antipsychotics are at least partially metabolized via the CYP2D6 isoenzymatic pathway. However, with the exception of risperidone (14), haloperidol (15–17) and clozapine (18, 19), little is known about the enzymatic pathways by which most of the antipsychotics are biotransformed. Thio- thixene, which differs structurally from the pheno- thiazines, is a good example of this. Investigators who conducted metabolism studies in the 1970s found that thiothixene is metabolized to a desmethyl and a sulfoxide metabolite (20), but the pathways that mediate these biotransformations are unknown at this time. This study is an investigation of the effect of paroxetine on thiothixene pharmacokinetics. MATERIALS AND METHODS All volunteers for this study were medically healthy, white, non-smokers between the ages of 18 and 65 years who were recruited using newspaper advertise- ments. This study protocol was approved by the University of Michigan Medical Centre Institutional Review Board, and upon agreement to participate in the study all volunteers signed a written informed consent form. Following a physical examination, clini- cal laboratory studies were conducted, including CBC, electrolytes, liver function studies, urinalysis and serum pregnancy tests for all pre-menopausal women. Volunteers did not have a history of any chronic Correspondence: Sally K. Guthrie, Associate Professor of Pharmacy, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, MI 48109–1065, U.S.A.  1997 Blackwell Science Ltd 221