Vol. 31, Issue 3, 243-249, March 2003

SHORT COMMUNICATION
Assessment of the Contributions of CYP3A4 and CYP3A5 in the Metabolism of the Antipsychotic Agent Haloperidol to Its Potentially Neurotoxic Pyridinium Metabolite and Effect of Antidepressants on the Bioactivation Pathway

Amit S. Kalgutkar, Timothy J. Taylor, Karthik Venkatakrishnan, and Emre M. Isin

Departments of Pharmacokinetics,Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, Connecticut (A.S.K., T.J.T., K.V.);
and Department of Chemistry,
Virginia Polytechnic Institute
and State University,
Blacksburg, Virginia (E.M.I)

As a plausible explanation for the large interindividual variability in the pharmacokinetics of the neuroleptic agent haloperidol, the contributions of CYP3A isozymes (CYP3A4 and the polymorphic CYP3A5) predominantly involved in haloperidol bioactivation to the neurotoxic pyridinium species 4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HPP⁺) were assessed in human liver microsomes and heterologously expressed enzymes. Based on recent reports on drug-drug interactions between haloperidol and antidepressants including selective serotonin reuptake inhibitors, the inhibitory effects of antidepressants on the CYP3A4/5-mediated haloperidol bioactivation were also evaluated. HPP⁺ formation followed Michaelis-Menten kinetics in microsomes, recombinant CYP3A4, and CYP3A5 with K_m values of 24.4 ± 8.9 µM, 18.3 ± 4.9 µM, and 200.2 ± 47.6 µM, respectively, and V_max values of 157.6 ± 13.2 pmol/min/mg of protein, 10.4 ± 0.6 pmol/min/pmol P450, and 5.16 ± 0.6 pmol/min/pmol P450, respectively. The similarity in K_m values between human liver microsomal and recombinant CYP3A4 incubations suggests that polymorphic CYP3A5 may not be an important genetic contributor to the interindividual variability in CYP3A-mediated haloperidol clearance pathways. Besides HPP⁺, a novel 4-fluorophenyl-ring-hydroxylated metabolite of haloperidol in microsomes/CYP3A enzymes was also detected. Its formation was consistent with previous reports on the detection of O-sulfate and -glucuronide conjugates of a fluorophenyl ring-hydroxylated metabolite of haloperidol in human urine. Finally, all antidepressants except buspirone inhibited the CYP3A4/5-catalyzed oxidation of haloperidol to HPP⁺ in a concentration-dependent manner. Based on the estimated IC₅₀ values for inhibition of HPP⁺ formation in microsomes, the antidepressants were ranked in the following order: fluoxetine, nefazodone, norfluoxetine, trazodone, and fluvoxamine. These inhibition results suggest that clinically observed drug-drug interactions between haloperidol and antidepressants may arise via the attenuation of CYP3A4/5-mediated 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol biotransformation pathways.