Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery.

Cytochrome P-450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the multidrug efflux pump, MDR or P-glycoprotein (P-gp), are present at high levels in the villus tip enterocytes of the small intestine, the primary site of absorption for orally administered drugs. These proteins are induced or inhibited by many of the same compounds and demonstrate a broad overlap in substrate and inhibitor specificities, suggesting that they act as a concerted barrier to drug absorption. A series of studies from our laboratory of cyclosporine and tacrolimus in humans and a novel cysteine protease inhibitor in rats, dosed concomitantly with inhibitors and inducers of CYP3A4 and P-gp, suggest that gut extraction can be modeled using measures of intestinal metabolism and absorption rate, the latter reflecting changes in P-gp. Results evaluating a preliminary model applied to the CYP3A substrate drugs midazolam, indinavir, saquinavir, and rifabutin suggest that the model may be useful for predicting in vivo intestinal metabolism from in vitro data.

[1]  J. Kolars,et al.  Interpatient heterogeneity in expression of CYP3A4 and CYP3A5 in small bowel. Lack of prediction by the erythromycin breath test. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[2]  J. Beijnen,et al.  Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. , 1997, British Journal of Cancer.

[3]  J. Lin,et al.  Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes. Major role of CYP3A. , 1997, Biochemical pharmacology.

[4]  Morton B. Brown,et al.  Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. , 1997, The Journal of clinical investigation.

[5]  L. Benet,et al.  Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction , 1992, Clinical pharmacology and therapeutics.

[6]  J. Palmer,et al.  Vinyl sulfones as mechanism-based cysteine protease inhibitors. , 1995, Journal of medicinal chemistry.

[7]  P. Watkins,et al.  Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[8]  A. Scialli.  Goodman and Gilman's the pharmacologic basis of therapeutics , 1991 .

[9]  J. Silverman,et al.  Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. , 1998, The Journal of pharmacology and experimental therapeutics.

[10]  M Rowland,et al.  Differentiation of absorption and first‐pass gut and hepatic metabolism in humans: Studies with cyclosporine , 1995, Clinical pharmacology and therapeutics.

[11]  Leslie Z. Benet,et al.  Effects of Ketoconazole on Digoxin Absorption and Disposition in Rat , 1998, Pharmacology.

[12]  T. Koudriakova,et al.  Metabolism of rifabutin in human enterocyte and liver microsomes: Kinetic parameters, identification of enzyme systems, and drug interactions with macrolides and antifungal agents , 1997, Clinical pharmacology and therapeutics.

[13]  M. E. Fitzsimmons,et al.  Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4: potential contribution to high first-pass metabolism. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[14]  L. Benet,et al.  Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: Implications for drug delivery and activity in cancer chemotherapy , 1995, Molecular carcinogenesis.

[15]  D. Shen,et al.  Oral first‐pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A‐mediated metabolism , 1996, Clinical pharmacology and therapeutics.

[16]  L. Benet,et al.  The effect of water‐soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers , 1996, Clinical pharmacology and therapeutics.

[17]  Malcolm Rowland,et al.  Clinical pharmacokinetics : concepts and applications , 1989 .

[18]  D. Shen,et al.  Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. , 1997, The Journal of pharmacology and experimental therapeutics.

[19]  L. Benet,et al.  Overlapping substrate specificities of cytochrome P450 3A and P-glycoprotein for a novel cysteine protease inhibitor. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[20]  L. Benet,et al.  Effects of ketoconazole on the intestinal metabolism, transport and oral bioavailability of K02, a novel vinylsulfone peptidomimetic cysteine protease inhibitor and a P450 3A, P-glycoprotein dual substrate, in male Sprague-Dawley rats. , 1998, The Journal of pharmacology and experimental therapeutics.

[21]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[22]  M. Rowland,et al.  Cyclosporin-erythromycin interaction in renal transplant patients. , 1989, British journal of clinical pharmacology.

[23]  D. Roden,et al.  The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. , 1998, The Journal of clinical investigation.

[24]  I. Pastan,et al.  Biochemistry of multidrug resistance mediated by the multidrug transporter. , 1993, Annual review of biochemistry.

[25]  P. Watkins,et al.  Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. , 1987, The Journal of clinical investigation.

[26]  Morton B. Brown,et al.  Role of intestinal P‐glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine , 1997, Clinical pharmacology and therapeutics.

[27]  L. Benet,et al.  Tacrolimus oral bioavailability doubles with coadministration of ketoconazole , 1997, Clinical pharmacology and therapeutics.

[28]  L. Benet,et al.  The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine , 1995, Clinical pharmacology and therapeutics.

[29]  I. Pastan,et al.  Expression of a multidrug-resistance gene in human tumors and tissues. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Leslie Z. Benet,et al.  Intestinal drug metabolism and antitransport processes : A potential paradigm shift in oral drug delivery , 1996 .

[31]  Y Zhang,et al.  Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. , 1998, Journal of pharmaceutical sciences.