Role of P-Glycoprotein and Organic Anion Transporting Polypeptides in Drug Absorption and Distribution
- 41 Downloads
Traditionally, drug-induced changes in cytochrome P450 isoenzyme activity, causing changes in drug metabolism and bioavailability, have been the main focus of drug interaction studies. Recent research, however, suggests that the drug transporters P-glycoprotein and organic anion transporting peptide (OATP), which can effect the efflux and influx of many classes of drugs, may contribute to drug interactions by mechanisms independent of oxidative metabolism. Experimental models designed to selectively probe the function of P-glycoprotein or OATP have demonstrated that changes in the activities of these transporters may have a significant effect on the bioavailability of clinically important drugs, leading to the potential for adverse drug interactions.
This review focuses on what is known about the P-glycoprotein and OATP drug transporters and their effects on drug bioavailability. Where possible, it uses as examples the second-generation Hi-receptor antagonists, where concomitant administration of other drugs or food constituents has been shown to alter the bioavailability of some agents of this class via mechanisms probably mediated by P-glycoprotein and/or OATP.
KeywordsDigoxin Terfenadine Loratadine Grapefruit Juice Fexofenadine
This publication was funded, in part, by an educational grant from the Schering-Plough Research Institute.
- 6.Banfield C, Cayen M, Gupta S, et al. Grapefruit juice has no effect on the bioavailability of desloratadine, but reduces the Cmax and AUC of fexofenadine by 30% [abstract]. Ann Allergy Asthma Immunol 2001; 86: 108Google Scholar
- 11.Silverman JA. P-glycoprotein. Metabolic drug interactions. Philadelphia: Lippincott Williams & Wilkins, 2000: 135–44Google Scholar
- 12.Fromm MF. P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Phannacol Ther 2000; 38: 69–74Google Scholar
- 16.Dresser GK, Scharwz U, Leake B, et al. Grapefruit juice selectively inhibits OATP not P-glycoprotein [abstract]. Drug Metab Rev 2000; 32Suppl. 2: 193Google Scholar
- 34.Dresser GK, Schwarz UI, Wilkinson GR, et al. St. John’s wort induces intestinal and hepatic CYP3A4 and P-glycoprotein in healthy volunteers [abstract]. Clin Pharmacol Ther 2001; 69:23Google Scholar
- 35.Harnman MA, Wang Z, Honig P, et al. Effects of acute and chronic Saint John’s wort (SJW) administration of fexofenadine (FEX) disposition [abstract]. Clin Pharmacol Ther 2001; 69: 53Google Scholar
- 51.Dresser GK, Schwarz UI, Leake B, et al. Citrus juices are potent inhibitors of intestinal OATP but not P-glycoprotein [abstract]. Clin Pharmacol Ther 2001; 69: 23Google Scholar
- 52.Bailey DG, Dresser GK, Munoz C, et al. Reduction of fexofenadine bioavailability by fruit juices [abstract]. Clin Pharmacol Ther 2001; 69: 21Google Scholar
- 59.Glue P, Banfield C, Affrime MB, et al. Lack of electrocardiographic interaction between desloratadine and erythromycin [abstract]. Allergy 2000; 55(Suppl. 63): 276Google Scholar
- 60.Affrime MB, Banfield C, Glue P, et al. Lack of electrocardiographic effects when desloratadine and ketoconazole are coadministered [abstract]. Allergy 2000; 55Suppl. 63: 277Google Scholar