A clinical drug-drug interaction between famotidine (a H 2 receptor antagonist) and probenecid has not been reproduced in rats. The present study hypothesized that the species-dependent probenecid sensitivity is due to a species difference in the contribution of renal organic anion and cation transporters. The transport activities of the H 2 receptor antagonists (cimetidine, famotidine, and ranitidine) by rat and human basolateral organic anion and cation transporters [human organic anion transporter (hOAT) 1, hOAT2, r/hOAT3, rat organic cation transporter (rOct) 1, and r/hOCT2] were compared using their cDNA transfectants. The transport activities (V max /K m ) of famotidine (K m , 345 M) by rOat3 were 8-and 15-fold lower than those of cimetidine (K m , 91 M) and ranitidine (K m , 155 M), respectively, whereas the activity by hOAT3 (K m , 124 M) was 3-fold lower than that of cimetidine (K m , 149 M) but similar to that of ranitidine (K m , 234 M). Comparison of the relative transport activity with regard to that of cimetidine suggests that famotidine was more efficiently transported by hOAT3 than rOat3, and vice versa, for ranitidine. Only ranitidine was efficiently transported by hOAT2 (K m , 396 M). rOct1 accepts all of the H 2 receptor antagonists with a similar activity, whereas the transport activities of ranitidine and famotidine (K m , 61/56 M) by r/hOCT2 were markedly lower than that of cimetidine (K m , 69/73 M). Probenecid was a potent inhibitor of r/OAT3 (K i , 2.6 -5.8 M), whereas it did not interact with OCTs. These results suggest that, in addition to the absence of OCT1 in human kidney, a species difference in the transport activity by hOAT3 and rOat3 accounts, at least in part, for the species difference in the drug-drug interaction between famotidine and probenecid.The kidney plays important roles in the detoxification of xenobiotics and endogenous wastes as well as maintaining the correct balance of ions and nutrients in the body. Urinary excretion is the major detoxification mechanism in the kidney, and this is governed by glomerular filtration, tubular secretion across the proximal tubules, and reabsorption. The renal uptake of organic anions and cations on the basolateral membrane of the proximal tubules has been characterized by multispecific organic anion and cation transporters (OAT/ SLC22 and OCT/SLC22), respectively (Lee and Kim, 2004;Wright and Dantzler, 2004;Shitara et al., 2005).Molecular cloning of basolateral transporters from different species allows examination of differences in their substrate specificities and transport activities, leading to a better understanding of the molecular mechanisms of species differences in drug disposition. For OCTs, the isoform expressed in the kidney differs between rodents and humans. Both Oct1 (Slc22a1) and Oct2 (Slc22a2) are involved in the renal uptake of organic cations on the basolateral membrane of the proximal tubules in rodents, whereas OCT2 is the predominant isoform in the human kidney (Koepsell, 2004;Lee and Kim, 2004;Wright a...

ABSTRACT:Fexofenadine is a selective, nonsedating H 1 -receptor antagonist approved for symptoms of allergic conditions, which is mainly excreted into feces via biliary excretion. The purpose of this study is to investigate its pharmacokinetics in mice and rats to determine the role of P-glycoprotein (P-gp) in its biliary excretion. In mice, biliary excretion clearance (17 ml/min/kg) accounted for almost 60% of the total body clearance (30 ml/min/kg). Comparing the pharmacokinetics after intravenous and oral administration indicated that the bioavailability of fexofenadine was at most 2% in mice. Knockout of Mdr1a/1b P-gp did not affect the biliary excretion clearance with regard to both plasma and liver concentrations, whereas the absence of P-gp caused a 6-fold increase in the plasma concentration after oral administration. In addition, the steady-state brain-to-plasma concentration ratio of fexofenadine was approximately 3-fold higher in Mdr1a/1b P-gp knockout mice than in wild-type mice. Together, these results show that P-glycoprotein plays an important role in efflux transport in the brain and small intestine but only a limited role in biliary excretion in mice. In addition, there was no difference in the biliary excretion between normal and hereditarily multidrug resistance-associated protein 2 (Mrp2)-deficient mutant rats (Eisai hyperbilirubinemic rats) and between wild-type and breast cancer resistance protein (Bcrp) knockout mice. These results suggest that the biliary excretion of fexofenadine is mediated by unknown transporters distinct from P-gp, Mrp2, and Bcrp.Fexofenadine is an orally active nonsedating histamine H1-receptor antagonist that is prescribed for oral treatment of allergic rhinitis and chronic idiopathic urticaria. After oral administration of [ 14 C]fexofenadine, the radioactivity was recovered in the urine (2.5%), bile (28%), and feces (69%) of rats whose bile duct had been cannulated, and thus, its oral absorption is at most 30%, and biliary excretion likely plays a major role in its elimination (Common Technical Document for the Registration of Pharmaceuticals for Human Use).It has been suggested that transporters play important roles in the disposition of fexofenadine. Fexofenadine has been shown to be a substrate of P-glycoprotein (P-gp) (Cvetkovic et al., 1999;Perloff et al., 2002). Vectorial transport of fexofenadine in the basal-to-apical direction was observed in Caco-2 cells, and this was inhibited by inhibitors of P-gp, such as ritonavir and verapamil (Perloff et al., 2002). Transfection of MDR1 P-gp cDNA into LLC-PK1 cells increased the vectorial transport of fexofenadine in the basal-to-apical direction (Cvetkovic et al., 1999). Furthermore, knockout of Mdr1a P-gp caused a significant increase in the plasma concentration of fexofenadine at 4 h after intravenous and oral administration. In addition, among the tissues examined, the brain-to-plasma concentration ratio of [ 14 C]fexofenadine compared with that in wild-type mice was also increased (Cvetkovic et al., 1999). The...

These results suggest that inhibition of hsp90 function, which causes depletion of hsp90 client proteins in tumor, contributes to the antitumor activity of KF58333, and that the stereochemistry of the oxime moiety is important for the biological activity of radicicol oxime derivatives.

Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.

These results suggest that monkey is a good predictor of the renal uptake of organic anions in the human.