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

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- Although, the neuroleptic agent haloperidol [HP 1 , 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-4-piperidinol] is one of the most widely used antipsychotic drugs, a narrow therapeutic index and a large interindividual and interracial variability in pharmacokinetics results in the requirement of individualized HP dose optimization (Ulrich et al., 1998). The narrow therapeutic index is associated with the frequent occurrence of extrapyramidal side effects including acute dystonic reactions, akathisia, Parkinsonism, and, following chronic treatment, tardive dyskinesias (TD) that are slow to develop and often irreversible (Wright et al., 1998). The persistence of TD in many patients after discontinuation of HP therapy suggests that this condition may be related to a neuronal lesion induced by HP or a reactive metabolite(s) derived from it.ChlorophenylHP is extensively metabolized in the liver with only ϳ1% of the administered dose excreted in the urine (Forsman et al., 1977). Major biotransformation pathways of HP in humans have been extensively characterized (see Kudo and Ishizaki, 1999 for a review) and are summarized in Fig. 1. These include 1) glucuronidation of the 3 0 alcohol moiety (Someya et al., 1992); 2) reduction of the carbonyl group by cytosolic carbonyl reductase, which leads to reduced HP (Eyles and Pond, 1992); 3) reverse oxidation of reduced HP back to HP (Pan et al., 1998); 4) N-dealkylation leading to the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP) (Fang et al., 2001); 5) dehydration of 3 0 alcohol moiety to 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP) (Subramanyam et al., 1991a;Van der Schyf et al., 1994) , 1997). In contrast to earlier studies (Llerena et al., 1992;Viala et al., 1996) that suggested the involvement of cytochrome P450 (P450) 2D6 in HP metabolism to CPHP, HPTP, and HPP ϩ , recent reports have indicated that these pathways are almost exclusively catalyzed by CYP3A4 (Usuki et al., 1996;Fang et al., 2001).In view of the neurotoxic properties of 1-methyl-4-phenylpyridinium (MPP ϩ ), the monoamine oxidase-B-generated metabolite of the Parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine , the identification of MPP ϩ -like HPP ϩ and RHPP ϩ metabolites in significant quantities in the urine (Subramanyam et al., 1991b), plasma (Avent et al., 1997, and post-mortem brain samples (Eyles et al., 1997) in schizophrenic patients treated with HP is of neurotoxicological importance especially in the pathogenesis of HP-induced TD. Additional support for this proposal is evident from the observations that HPP ϩ displays MPP ϩ -like neurotoxicity in vivo as well as in vitro (Bloomquist et al., 1994).Although glucuronidat...

Heterotropic Activation of the Midazolam Hydroxylase Activity of CYP3A by a Positive Allosteric Modulator of mGlu5: In Vitro to In Vivo Translation and Potential Impact on Clinically Relevant Drug-Drug Interactions

“…Human donor pools were mixed sex/mixed age; rat pools were male Sprague-Dawley. (Fang et al, 2001;Kalgutkar et al, 2003;Avent et al, 2006). Importantly, HAL was also found to be back-oxidized from RHAL in vitro.…”

“…Many of these drugs, including haloperidol (HAL), are metabolized either exclusively or to a great extent by CYP3A4 (Fang et al, 2001;Kalgutkar et al, 2003;Avent et al, 2006). CYP3A4 is predominantly expressed in the liver, and to a lesser extent in the intestine, and is involved in the metabolism of a wide variety of drugs, xenobiotics, and steroids (Thummel and Wilkinson, 1998;Guengerich, 2006).…”

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…No significant response associations have been reported with the polymorphic CYP3A5, an enzyme reported to contribute to antipsychotic metabolism. 44,63,76 Several variants related to decreased activity of CYP2C9 and CYP2C19 have been detected, 77,78 and one CYP2C19 variant (*17) with increased transcription in vitro has been described. 77 Aside from lower dose requirements, 28,79 no connection between these variants and level of response to psychotropic drugs has been reported.…”

Pharmacogenetics of Schizophrenia: Bringing ‘Order to Chaos' in the Psychopharmacology of Schizophrenia?

“…To date, no significant reports of an association of the identified variants of CYP3A4 with antipsychotic variability or response have been published. Likewise no signifi-cant response associations have been reported with the polymorphic CYP3A5, an enzyme reported to contribute to antipsychotic metabolism [64] .…”