Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism
Open Access
- 8 June 2006
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 318 (3), 1220-1229
- https://doi.org/10.1124/jpet.106.106013
Abstract
The contribution of the gut is not routinely incorporated into in vitro-in vivo predictions of either clearance or drug-drug interactions, and this omission may partially explain the general underprediction trend often observed. In the current study, the metabolic ability of hepatic and intestinal pooled microsomes was compared for eight CYP3A substrates (midazolam, triazolam, diazepam, alprazolam, flunitrazepam, nifedipine, testosterone, and quinidine) and paclitaxel, tolbutamide, S-mephenytoin, and bufuralol as CYP2C8, CYP2C9, CYP2C19, and CYP2D6 probes, respectively. A general agreement in the type of kinetics was observed between the two systems for the substrates investigated. Of the 16 pathways investigated, 75% of Km (S50) values obtained in intestinal microsomes (5.9-769 μM) were within 2-fold of hepatic estimates. Irrespective of the cytochrome P450 (P450) investigated and normalization of Vmax values for the P450 abundance, clearance was 4.5- to 50-fold lower in intestinal microsomes (0.0005-0.51 μl/min/P450) compared with the hepatic estimates (0.002-5.8 μl/min/P450), whereas the rank order was consistent between the systems. Assessment of two enterocyte isolation methods (mucosal scraping or enterocyte elution) was performed at the substrate concentrations corresponding to the determined Vmax conditions for 11 pathways. The activity difference between the methods (3-29-fold) was P450-related in the following rank order: CYP2C19 > CYP3A4 > CYP2C9 ∼ CYP2D6. After correction for the loss of activity between the methods, the intrinsic activities of hepatic and intestinal CYP3A4, CYP2C9, CYP2C19, and CYP2D6 were comparable for the 16 pathways. The implications of these findings on the prediction of intestinal first-pass metabolism are discussed.This publication has 26 references indexed in Scilit:
- THE HUMAN INTESTINAL CYTOCHROME P450 “PIE”Drug Metabolism and Disposition, 2006
- CHARACTERIZATION OF RAT SMALL INTESTINAL AND COLON PRECISION-CUT SLICES AS AN IN VITRO SYSTEM FOR DRUG METABOLISM AND INDUCTION STUDIESDrug Metabolism and Disposition, 2005
- Microsomal prediction ofin vivoclearance and associated interindividual variability of six benzodiazepines in humansXenobiotica, 2005
- UTILITY OF RECOMBINANT ENZYME KINETICS IN PREDICTION OF HUMAN CLEARANCE: IMPACT OF VARIABILITY, CYP3A5, AND CYP2C19 ON CYP3A4 PROBE SUBSTRATESDrug Metabolism and Disposition, 2004
- Unmasking the dynamic interplay between efflux transporters and metabolic enzymesInternational Journal of Pharmaceutics, 2004
- MODELING OF INTESTINAL DRUG ABSORPTION: ROLES OF TRANSPORTERS AND METABOLIC ENZYMES (FOR THE GILLETTE REVIEW SERIES)Drug Metabolism and Disposition, 2003
- CYP3A4-Transfected Caco-2 Cells as a Tool for Understanding Biochemical Absorption Barriers: Studies with Sirolimus and MidazolamThe Journal of pharmacology and experimental therapeutics, 2003
- MULTISITE KINETIC ANALYSIS OF INTERACTIONS BETWEEN PROTOTYPICAL CYP3A4 SUBGROUP SUBSTRATES: MIDAZOLAM, TESTOSTERONE, AND NIFEDIPINEDrug Metabolism and Disposition, 2003
- Clinical Pharmacokinetics of AtorvastatinClinical Pharmacokinetics, 2003
- Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extractionAdvanced Drug Delivery Reviews, 1997