P-glycoprotein transporters

M. F., Wilkinson, G. R., Kim, R. B., OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine, Drug Metab. Dispos. 1999, 27, 866-871. 

Martel, F., Martins, M. J., Hipolito-Reis, C., Azevedo, I., Inward transport of [3H]-l-mefhyl-4-phenyl-pyridinium in rat isolated hepatocytes putative involvement of a P-glycoprotein transporter, Br. J. Pharmacol. 1996, 119, 1519-1524. 

Cvetkovic M, Leake B, Fromm MF, Wilkinson GR and Kim RB (1999) OATP and P-Glycoprotein Transporters Mediate the Cellular Uptake and Excretion of Fexofenadine. Drug Metab Dispos 27 pp 866-871. 

Kawazu K, Yamada K, Nakamura M, Ota A. Characterization of cyclosporin a transport in cultured rabbit corneal epithelial cells P-glycoprotein transport activity and binding to cyclophilin. Invest Ophthalmol Vis Sci 40 1738-1744 (1999). 

Certain Hi antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other mediators of inflammation. This action is not due to H -receptor blockade and may reflect an H4-receptor effect (see below). The mechanism is not fully understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few H4 antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain. The significance of this effect is not known. 

Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces P-glycoprotein transporter and thus may alter the disposition of many other drugs (Table 49-4). Concurrent administration of tipranavir with fosamprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs. Tipranavir/ritonavir may also decrease serum levels of valproic acid and omeprazole. Levels of lovastatin, simvastatin, atorvastatin, and rosuvastatin may be increased, increasing the risk for rhabdomyolysis and myopathy. 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichel-baum M, Fritz P, Burk O, Decker J, Aiken P, Rothenpieler U, Kerb R, Hoff-meyer S, Brauch H. Association of the P-glycoprotein transporter MDR1 (C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 2002 13 1847-1854. 

Sasongko L, Link JM, Muzi M, et al. Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther 2005 77 503-514. 

Choo EF, Leake B, Wandel C, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000 28 655-660. 

Ueda K, Okamura N, Hirai M, et al. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 1992 267... 

Spahn-Langguth H, Baktir G, Radschuweit A, et al. P-glycoprotein transporters and the gastrointestinal tract evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. Int J Clin Pharmacol Ther 1998 36 (l) 16-24. 

Perloff ES, Duan SX, Skolnik PR, et al. Atazanavir effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos 2005 33 764-770. 

Terfenadine is at least 70% absorbed after oral administration but is rapidly metabolized by first-pass metabolism to fexofenadine (terfenadine carboxylate) and an inactive dealkylated product. Metabolism appears to be mediated entirely by the CYP (CYP3A4). Fexofenadine is about 70% protein bound and exhibits biphasic elimination with an initial plasma half-life of 3.5 hours and a terminal plasma half-life of 6 to 12 hours. Fexofenadine is excreted mostly unchanged (80% in feces, 12% in urine), with <10% converted to inactive metabolites (7). Fexofenadine excretion can be affected by compounds (e.g., ketoconazole) that interact with the P-glycoprotein transporter because fexofenadine is a substrate for this transporter (8). 

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