title: 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.
abstract: 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 microM, 18.3 +/- 4.9 microM, and 200.2 +/- 47.6 microM, 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 IC(50) 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.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. amit_kalgutkar@groton.pfizer.com
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Taylor
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Emre M
authors.initials: EM
authors.lastname: Isin
mesh_terms: D000928:Antidepressive Agents / Q000378:metabolism*; D014150:Antipsychotic Agents / Q000737:chemistry / Q000378:metabolism; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D011726:Pyridinium Compounds / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D011726:Pyridinium Compounds; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006220:Haloperidol