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acin) were administered simultaneously. , 9 In addition, the biliary excretion of P-glycoprotein substrates was shown to depend on the expression level of this protein, and a significant increase in the biliary excretion of vinblastine was observed in rats with increased levels of P-glycoprotein, which was induced by 2-acetylami-nofluorene and phenothiazine, respectively, in two independent studies.140,141 These data suggest that P-glycoprotein plays an important role in biliary excretion. However, other studies have failed to find significant effects on P-glycoprotein-mediated biliary excretion in knockout mice. For example, while the intestinal secretion and bioavailability of paclitaxel were markedly altered in mdrla (-/-) knockout mice, the biliary excretion of this model substrate in the knockout mice was not significantly different from that in the wild-type animals.118 Even in the mdrla/lb (-/-) double knockouts, the biliary excretion of both digoxin and vinblastine was not substantially changed.114 One possible explanation of these conflicting results is the presence of alternative transport processes responsible for the secretion of these substrates into bile. P-glycoprotein may act in concert with other transporters in excreting certain substrates into bile, and the loss of P-glycoprotein function could be compensated for by other transport processes under certain circumstances. Indeed, it has been shown that mdrlb expression in the liver and kidney was consistently increased in mdrla (-/-) knockout mice compared to the wild-type animals, indicating that the loss of mdrla function could be compensated for by mdr1b protein for their common substrates.113 Other canalicular membrane transporters may also exhibit overlapping substrate specificity for certain P-glycoprotein substrates.

Renal clearance represents an important route for the elimination of a large number of xenobiotic compounds. This dynamic process includes glomerular filtration, renal tubular secretion, and tubular reabsorption. Renal secretion usually takes place against a concentration gradient and thus is mainly an active process involving a variety of transporter mechanisms.142 In addition to the two major carrier systems responsible for the renal handling of organic cations and organic anions, several ATP-dependent transporters, including P-glycoprotein and MDR-associated proteins, have been detected in the kidney.142 The transport function and the localization of P-glycoprotein on the apical membrane of the proximal tubule cells106 suggest the involvement of this protein in the renal secretion of its substrates into urine. The observation that a classic P-glycoprotein inhibitor, cyclosporin, decreased colchicine renal clearance after IV administration from 6.23 ± 0.46 to 3.58 ± 0.31 ml/(min • kg) (mean ± SD; p < .05) without affecting glomerular filtration and the secretion of the organic cation ranitidine or the organic anion p-ami-nohippurate, provided the first in vivo demonstration for this functional role of P-glycoprotein.143 Subsequently, a significant reduction of the renal secretion of digoxin (in rats), vinblastine, and vincristine (in dogs) by cyclosporin A was also observed by using the isolated perfused rat kidney or the single-pass multiple indicator dilution method.144,145 In humans, the renal clearance of digoxin was decreased 20% by the concomitant use of itraconazole (p < .01). Since digoxin is mainly excreted unchanged into urine, this reduction is most likely mediated by the inhibition of P-glycoprotein.146 Similarly, the renal clearance of quinidine was also decreased by 50% (p < .001) by itraconazole in a double-blind, randomized, two-phase crossover study, and inhibition of P-glycoprotein is thought to be the most likely underlying mechanism.147 Taken together, these studies demonstrated that P-glycoprotein significantly contributes to the renal excretion of its substrates.

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