Role of Small Intestinal Cytochromes P450 in the Bioavailability of Oral Nifedipine

Abstract

ABSTRACT:To determine the effect of intestinal cytochrome P450 (P450) enzymes on the bioavailability of oral drugs, we have examined the metabolism of nifedipine, an antihypertensive drug and a model substrate of CYP3A4, in mouse models having deficient expression of the NADPH-cytochrome P450 reductase. Initial studies were performed on Cpr-low (CL) mice, which have substantial decreases in Cpr expression in all tissues examined, including the small intestine. In CL mice, area under the concentration-time curve (AUC) values for blood nifedipine after intraperitoneal and oral dosing were 1.8-and 4.0-fold, respectively, higher than in wild-type mice, despite increased expression of multiple P450 enzymes in both liver and intestine. The greater extent of the increase in the AUC value for oral than for intraperitoneal nifedipine suggested that intestinal P450s influence the bioavailability of oral nifedipine, a notion supported by results from further studies on LCN and CL-LCN mice. The LCN mice, which have liver-specific Cpr deletion, had 6.9-fold higher AUC values and 2.2-fold higher C max values for blood nifedipine than did wild-type mice after oral nifedipine, consistent with the critical role of hepatic P450s in systemic nifedipine clearance. However, in the CL-LCN mice, which have global decreases in Cpr expression in all tissues examined and Cpr deletion in the liver, AUC and C max values for oral nifedipine were, respectively, 2.2-and 1.8-fold higher than in LCN mice, confirming the fact that P450-catalyzed metabolism in the small intestine, the portal-of-entry organ for oral drugs, plays an important role in the first-pass clearance of oral nifedipine.

Gene Expression Profiling of Systems Involved in the Metabolism and the Disposition of Xenobiotics: Comparison between Human Intestinal Biopsy Samples and Colon Cell Lines

“…Apart from data for cytochromes P450 (Obach et al, 2001;Bergheim et al, 2005;Zhang et al, 2007), available data on other genes expressed in human intestinal tissues are very limited (Kaminsky and Zhang, 2003;Anderle et al, 2004;Hilgendorf et al, 2007). Hierarchical clustering revealed that profiles of ileal biopsy samples were separated from profiles of colon biopsy samples.…”

Metabolism of Saikosaponin a in Rats: Diverse Oxidations on the Aglycone Moiety in Liver and Intestine in Addition to Hydrolysis of Glycosidic Bonds

“…SSa and M13-M17 excreted through the bile duct were metabolized further in the intestine, according to their disappearance in the feces. In the intestine, SSa was metabolized through hydrolysis mediated by the intestinal flora following oxidation catalyzed by the metabolizing enzymes in the intestinal mucosal cells (Kaminsky and Zhang, 2003;Zhang et al, 2007). Both the renal and biliary routes were observed for the excretion of SSa and its metabolites.…”

Metabolite Kinetics: The Segregated Flow Model for Intestinal and Whole Body Physiologically Based Pharmacokinetic Modeling to Describe Intestinal and Hepatic Glucuronidation of Morphine in Rats In Vivo

“…The direct observations on intestinal metabolism could be deciphered for lorcainide metabolism in portacaval shunts in rodents (Gugler et al, 1975;Giacomini et al, 1980;Plänitz, et al, 1985) and midazolam oxidation in anhepatic patients after duodenal and intravenous administrations during transplant surgery (Paine et al, 1996). Others examined specific gene knockdown of Cyp3a and NADPH-cytochrome P450 reductase within the intestinal versus hepatic tissue to directly demonstrate the effect of the knockdown of intestinal versus liver enzymes in first-pass metabolism in vivo (van Herwaarden et al, 2007;Zhang et al, 2007Zhang et al, , 2009. The method of comparison of plasma or blood AUCs of drug after oral, intraportal, and intravenous administration, supplemented by in vitro metabolic data, is commonly used to identify the presence of intestinal and extrahepatic versus liver drug metabolism (Iwamoto and Klaassen, 1977;Iwamoto et al, 1982;Cassidy andHouston, 1984, Mistry andHouston, 1987;Liu et al, 2010).…”

“…In contrast, physiologically based pharmacokinetic (PBPK) models address events of sequential elimination and include transmembrane barriers Pang, 1986, 1993;Pang, 2003;Pang et al, 2009;Chow and Pang, 2013) and transporters (Sun et al, 2006. The intestine, richly endowed with enzymes and transporters (van Herwaarden et al, 2007;Zhang et al, 2007Zhang et al, , 2009Liu et al, 2010), strongly affects firstpass metabolism and controls the flow of substrate to the liver (Pang and Chow, 2012). Intestinally formed metabolites may undergo immediate sequential metabolism or excretion (Pang and Gillette, 1979).…”