Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

Badhan, Raj; Penny, Jeffrey; Galetin, Aleksandra; Houston, J. Brian

doi:10.1002/jps.21572

Cited by 45 publications

(47 citation statements)

References 69 publications

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“…Wu (2012) has recently commented, in a theoretical examination, that heterogeneity matters in predicting F sys after comparison of simulations from the TM-PBPK and SSFM-PBPK models on the systemic availability of the parent aglycone during the process of enterohepatic circulation of biliarily excreted glucuronides. The consideration of heterogeneity of transporters and enzymes on intestinal modeling in vivo surfaced much later, possibly due to the difficulty in obtaining population and length-averaged estimates on physiological dimensions of the lumen, surface area, flow, and enzymes and transporters in humans and animals (Badhan et al, 2009;Bruyère et al, 2010). Other compartmental models, when coupled with a refined description on the linear transfer kinetics of state properties of the drug (unreleased or solid form, undissolved or aggregate form, and dissolved or solution form), physicochemical properties (pKa, solubility, particle size, particle density, and permeability), physiological properties (gastric emptying, intestinal transit rate, intestinal metabolism, and luminal transport), and dosage factors (dosage form and dose), in the gastrointestinal tract show much improved predictions of drug kinetics (Agoram et al, 2001;Hendriksen et al, 2003), especially with inclusion of heterogeneity factors in the modeling (Bolger et al, 2009;Abuasal et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Pang

Chow

2012

Drug Metab Dispos

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ABSTRACT:Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the intestinal availability (F I ) and, in turn, the systemic availability (F sys ) and intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (Q Gut ) model stipulate that 1.0, ϳ0.05 to 0.3, and <0.484؋ of the total intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (f Q ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the Q Gut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < Q Gut model < TM in the description of F I , and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to firstpass removal was the opposite: SFM > Q Gut model > TM. The findings suggest that the f Q value strongly influences the rate of intestinal metabolism (F I and F sys ) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the f Q value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.

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Section: Discussionmentioning

confidence: 99%

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Pang

Chow

2012

Drug Metab Dispos

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“…However, Tam et al (2003) and Knight et al (2006), based on theoretical considerations, suggested that P-gp would decrease the rate of CYP3A-mediated metabolism under nonsaturating conditions by reducing the intracellular concentration of the substrate. Thus, the conclusion that P-gp enhances the metabolism of dual P-gp/ CYP3A substrates during absorption based on experimental results from Caco-2 cell model (Gan et al, 1996;Hochman et al, 2000;Cummins et al, 2001Cummins et al, , 2002Cummins et al, , 2003Cummins et al, , 2004Johnson et al, 2001;Li et al, 2002;Benet et al, 2004) or single-pass rat intestinal perfusion model (Cummins et al, 2003) is contradicted by an opposite conclusion reached based on pharmacokinetic modeling studies and theoretical considerations (Tam et al, 2003;Badhan et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism

et al. 2013

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P-glycoprotein (P-gp) and CYP3A (cytochrome P450 3A, generally; Cyp3a, rodent enzyme) in the intestine can attenuate absorption of orally administered drugs. While some suggest that P-gp enhances intestinal metabolism by CYP3A/Cyp3a during absorption of a dual substrate, others suggest that P-gp reduces the metabolism in the intestine when substrates are at subsaturating concentrations. Hence, to elucidate the cellular mechanisms that can address these divergent reports, we studied intestinal absorption of the dual substrate loperamide in portal vein-cannulated P-gp-competent and P-gp-deficient mice. These studies showed that at low doses of loperamide, which produced intestinal concentrations near the apparent K m for oxidative metabolism, the bioavailability across the intestine (F G ) was 6-fold greater in the P-gp-competent mice than in P-gp-deficient mice. The higher F G of loperamide in the presence of P-gp was attributed to lower loperamide intestinal metabolism. However, at high doses of loperamide, the sparing of first-pass metabolism by P-gp was balanced against the attenuation of absorption by apical efflux, resulting in no net effect on F G . In vitro studies with intestinal tissue from P-gp-competent and -deficient mice confirmed that P-gp reduced the metabolic rate of loperamide during absorptive flux at concentrations near K m but had little effect on metabolism at higher (saturating) concentrations. Further, studies in which Cyp3a was chemically inactivated by aminobenzotriazole in P-gp-competent and -deficient mice, showed that P-gp and Cyp3a individually attenuated F G by 8-fold and 70-fold, respectively. These results confirmed that P-gp effectively protects loperamide at low doses from intestinal first-pass metabolism during intestinal absorption.

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“…These are based on the incorporation of drug permeability and metabolism data and enterocytic blood flow together with zonal and cellular heterogeneous distribution of metabolic enzyme and efflux/ uptake transporters along the length of the intestine (Ito et al, 1999;Tam et al, 2003;Badhan et al, 2009;Jamei et al, 2009). In contrast to complex physiologically based models, a "minimal" Q Gut model has been proposed.…”

mentioning

confidence: 99%

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

Gertz

Harrison²,

Houston³

et al. 2010

Drug Metab Dispos

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270

233

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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.

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Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

Cited by 45 publications

References 69 publications

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism

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

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Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

Cited by 45 publications

References 69 publications

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

P-Glycoprotein Increases Portal Bioavailability of Loperamide in Mouse by Reducing First-Pass Intestinal Metabolism

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

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Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel