Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability

doi:10.1002/jps.20309

Journal of Pharmaceutical Sciences

Volume 94, Issue 8, August 2005, Pages 1694-1704

https://doi.org/10.1002/jps.20309 Get rights and content

Abstract

The purpose of this study is to determine the functional role of P-glycoprotein (P-gp) in intestinal absorption of drugs and to quantitatively predict the in vivo absorption enhancement on P-gp inhibition. In situ single-pass rat ileum permeability and aqueous solubility were measured for a set of 16 compounds. Permeability studies were also carried out in the presence of P-gp inhibitor to estimate the permeability enhancement on P-gp inhibition. A significant correlation was obtained between rat ileum permeability and the literature human intestinal absorption (HIA), F_a,human (r = 0.891; p < 0.01). Compounds with permeability >0.2 × 10⁻⁴ cm/s are completely absorbed; however, few practically insoluble compounds were overestimated with this relationship. Inhibition of P-gp increased the permeability (p < 0.05) of three moderately and three highly permeable compounds. Efflux inhibition ratio (EIR), the ratio of permeability due to P-gp-mediated efflux activity and passive permeability only, for these compounds was in the order of digoxin > paclitaxel > fexofenadine > quinidine > verapamil > cyclosporine. Integration of EIR with permeability versus F_a,human predicted that modulation of P-gp has no significant effect on the absorption of highly permeable compounds (quinidine, verapamil, and cyclosporine A), while for moderately permeable compounds (digoxin, paclitaxel, and fexofenadine), P-gp profoundly influences the intestinal permeability. The in situ permeability in rat ileum may be used to predict the in vivo P-gp function and its quantitative contribution to intestinal drug absorption. Integration of the functional activity of P-gp with the characteristics of BCS may explain drug interactions and explore the possible pharmacokinetic advantage on P-gp inhibition.

Section snippets

INTRODUCTION

There is increasing evidence that P-glycoprotein (P-gp) have a much broader substrate specificity and a number of drugs, including HIV protease inhibitors like indinavir, saquinavir, ritonavir, and anticancer drugs like paclitaxel and vinblastin h ave been reported to be substrates for P-gp using in vitro methodologies.¹^,² The significant expression of P-gp in normal intestine raises the questions of its functional role and of whether it can influence the drug absorption processes. In vivo

Chemicals

Paclitaxel and cyclosporine were a gift from Dabur India Ltd. (New Delhi, India). Fexofenadine HCl and hydrochlorthiazide were received from Aristo Pharmaceuticals Ltd. (Daman, India). Indinavir sulphate and lovastatin were generously provided by Matrix Lab. Ltd. (Hyderabad, India). Propranolol HCl was from Sun Pharmaceutical Industries Ltd. (Mumbai, India). Digoxin was gifted by Burroughs Wellcome India Ltd. (Mumbai, India). Frusemide and ranitidine were from Dr. Reddys' Lab. (Hyderabad,

Solubility and Permeability Determinations

Permeability (P_eff,Control) was determined in rat ileum using in situ single-pass perfusion technique. The P_eff,Control values ranged from 0.009 ± 0.006 × 10⁻⁴ cm/s to 1.30 ± 0.24 × 10⁻⁴ cm/s with lovastatin showing least and l-phenylalanine, the maximum permeability (Table 1). Equilibrium solubility determined by shake-flask method or taken from the literature, and/or in situ permeability data was used to estimate maximum absorbable dose (MAD), an indicative of the maximum amount of drug that can be

DISCUSSION

The extent of interaction with P-gp, the passive permeability, and the overall effective permeability of drugs determines the quantitative functional role of P-gp in limiting intestinal absorption in vivo. In the present study, we have quantitatively estimated the enhancement in HIA when P-gp-mediated efflux transport is inhibited, by using in situ intestinal perfusion model in Sprague-Dawley rats.

The selected compounds (excluding cyclosporine and paclitaxel) demonstrated close agreement in

CONCLUSIONS

Equilibrium solubility and in situ permeability in rats were determined for a set of 16 compounds. The in situ permeability showed a significant correlation to F_a,human. Compounds can be classified according to BCS based on the limits of 0.2 × 10⁻⁴ cm/s for high permeability and the dose number <1 for high solubility. Incompletely absorbed compounds from the dataset were found to be solubility and/or permeability limiting. Inhibition of P-gp has moved compounds of BCS class III and IV (digoxin,

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Prediction of in vivo intestinal absorption enhancement on P-glycoprotein inhibition, from rat in situ permeability

Abstract

Section snippets

INTRODUCTION

Chemicals

Solubility and Permeability Determinations

DISCUSSION

CONCLUSIONS

Pharmacol Res

Adv Drug Deliv Rev

Adv Drug Deliv Rev

Eur J Pharm Sci

J Chromatogr B Anal Technol Biomed Life Sci

J Chromatogr B Anal Technol Biomed Life Sci

J Chromatogr B

J Allergy Clin Immunol

Biochem Biophys Res Commun

J Pharm Sci

J Pharm Sci

Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors

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