QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalgutkar, A. S. Articles by Nguyen, H. T. Search for Related Content PubMed PubMed Citation Articles by Kalgutkar, A. S. Articles by Nguyen, H. T.

IDENTIFICATION OF AN N-METHYL-4-PHENYLPYRIDINIUM-LIKE METABOLITE OF THE ANTIDIARRHEAL AGENT LOPERAMIDE IN HUMAN LIVER MICROSOMES: UNDERLYING REASON(S) FOR THE LACK OF NEUROTOXICITY DESPITE THE BIOACTIVATION EVENT

Discovery Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, Connecticut

In contrast with the Parkinson's-like effects associated with the mitochondrial neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the neuroleptic agent haloperidol, there exist no reports on adverse central nervous system (CNS) effects with the structurally related N-substituted-4-arylpiperidin-4-ol derivative and antidiarrheal agent loperamide. Although this difference can be attributed to loperamide's P-glycoprotein substrate properties that prevent it from accessing the brain, an alternative possibility is that loperamide metabolism in humans is different from that of MPTP and haloperidol and does not involve bioactivation to a neurotoxic pyridinium species. In the current study, loperamide bioactivation was examined with particular focus on identification of pyridinium metabolites. A NADPH-dependent disappearance of loperamide was observed in both rat and human liver microsomes (human t_1/2 = 13 min; rat t_1/2 = 22 min). Loperamide metabolism was similar in human and rat and involved N-dealkylation to N-desmethylloperamide (M3) as the principal metabolic fate. Other routes of loperamide biotransformation included N- and C-hydroxylation to the loperamide-N-oxide (M4) and carbinolamide (M2) metabolites, respectively. Furthermore, the formation of an additional metabolite (M5) was also discernible in human and rat liver microsomes. The structure of M5 was assigned to the pyridinium species (LPP⁺) based on comparison of the liquid chromatography/tandem mass spectrometry characteristics to the pyridinium obtained from loperamide via a chemical reaction. Loperamide metabolism in human microsomes was sensitive to ketoconazole and bupropion treatment, suggesting P4503A4 and -2B6 involvement. Recombinant P4503A4 catalyzed all of the loperamide biotransformation pathways in human liver microsomes, whereas P4502B6 was only responsible for N-dealkylation and N-oxidation routes. The wide safety margin of loperamide (compared with MPTP and haloperidol) despite metabolism to a potentially neurotoxic pyridinium species likely stems from a combination of factors that include a therapeutic regimen normally restricted to a few days and the fact that loperamide and perhaps LPP⁺ are P-glycoprotein substrates and are denied entry into the CNS. The differences in safety profile of haloperidol and loperamide despite a common bioactivation event supports the notion that not all compounds undergoing bioactivation in vitro will necessarily elicit a toxicological response in vivo.

This article has been cited by other articles:

				S. S. Zoghbi, J.-S. Liow, F. Yasuno, J. Hong, E. Tuan, N. Lazarova, R. L. Gladding, V. W. Pike, and R. B. Innis 11C-Loperamide and Its N-Desmethyl Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux J. Nucl. Med., April 1, 2008; 49(4): 649 - 656. [Abstract] [Full Text] [PDF]

				J. H. Chang, C. J. Kochansky, and M. Shou The Role of P-glycoprotein in the Bioactivation of Raloxifene Drug Metab. Dispos., December 1, 2006; 34(12): 2073 - 2078. [Abstract] [Full Text] [PDF]

				J.-D. Marechal, J. Yu, S. Brown, I. Kapelioukh, E. M. Rankin, C. R. Wolf, G. C. K. Roberts, Mark. J. I. Paine, and M. J. Sutcliffe IN SILICO AND IN VITRO SCREENING FOR INHIBITION OF CYTOCHROME P450 CYP3A4 BY COMEDICATIONS COMMONLY USED BY PATIENTS WITH CANCER Drug Metab. Dispos., April 1, 2006; 34(4): 534 - 538. [Abstract] [Full Text] [PDF]

				M. Shebley, M. I. Jushchyshyn, and P. F. Hollenberg SELECTIVE PATHWAYS FOR THE METABOLISM OF PHENCYCLIDINE BY CYTOCHROME P450 2B ENZYMES: IDENTIFICATION OF ELECTROPHILIC METABOLITES, GLUTATHIONE, AND N-ACETYL CYSTEINE ADDUCTS Drug Metab. Dispos., March 1, 2006; 34(3): 375 - 383. [Abstract] [Full Text] [PDF]

				G. Mukwaya, T. MacGregor, D. Hoelscher, T. Heming, D. Legg, K. Kavanaugh, P. Johnson, J. P. Sabo, and S. McCallister Interaction of Ritonavir-Boosted Tipranavir with Loperamide Does Not Result in Loperamide-Associated Neurologic Side Effects in Healthy Volunteers Antimicrob. Agents Chemother., December 1, 2005; 49(12): 4903 - 4910. [Abstract] [Full Text] [PDF]