Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

Abstract

ABSTRACT:Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (F G ) from in vitro metabolic clearance and permeability data of 25 drugs using the Q Gut model. The drug selection included a wide range of physicochemical properties and in vivo F G values (0.07-0.94). In vitro clearance data (CLu int ) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n ‫؍‬ 105 donors) using the substrate depletion method. Apparent drug permeability (P app ) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH ‫؍‬ 7.4). In addition, effective permeability (P eff ) data, estimated from regression analyses to P app or physicochemical properties were used in the F G predictions. Determined CLu int values ranged from 0.022 to 76.7 l/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu int values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F G predictions were most successful when P app data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F G underpredictions. Good agreement between predicted and in vivo F G was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted F G value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F G <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F G is 6% of the observed value). Implications of the findings are discussed.

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 emergence of the Q Gut model (Yang et al, 2007) and the advanced dissolution, absorption, metabolism model from Simcyp (Darwich et al, 2010) favors this concept of partial flow. Other models that further encompass heterogeneity in transporters and enzymes have been adopted to explain the lesser intestinal metabolism observed for drugs given systemically versus orally (Tam et al, 2003;Liu et al, 2006;Bruyère et al, 2010;Gertz et al, 2010) as well as the effect of enterohepatic circulation of glucuronide conjugates (Wu, 2012). Undoubtedly, our PBPK investigation strongly supports the SFM for intestinal modeling.…”

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…Those jejunal P eff values are currently limited to only 30 drugs (3)(4)(5). Therefore, its application to drugs not listed in the current datasets depends on the availability of in vivo, in vitro or in silico methods for the prediction of jejunal P eff (59,60,(77)(78)(79)(80)(81)(82). Due to the use of P eff for this study, regional differences in the transport mechanisms of the drugs involved herein were not explicitly considered (e.g.…”

Characterization of In Vitro Glucuronidation Clearance of a Range of Drugs in Human Kidney Microsomes: Comparison with Liver and Intestinal Glucuronidation and Impact of Albumin

“…Intersubject variability for CL i.v. and f u, p was (Ito and Houston, 2005;Gertz et al, 2010). Clearance via metabolism was corrected for the fraction metabolized by glucuronidation (f m, UGT ) to give the apparent in vivo glucuronidation clearance (CL UGT ).…”

“…Similar comparisons were made using data in the absence of BSA. Prediction bias and precision were assessed using geometric fold error and root mean squared error, respectively, as described previously (Gertz et al, 2010).…”