Drug interactions transport

Shitara Y, Sato H, Sugiyama Y (2005) Evaluation of drug-drug interactions in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol 45 689-723... 

Neuhoff, S., Zamora, I., Ungell, A.-L., Artursson, P., pH-dependent bidirectional transport of weak basic drugs across Caco-2 cell monolayers, implications for drug-drug interactions, 2002 Pharm. Res. (submitted). 

Tukker, G., Houston, J. B., Huang, S.-M., Optimizing drug development strategies to assess drug metabolism/ transporter interaction potential — toward a consensus, Clin. Pharmacol. Ther. 2001, 70, 103-114. 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

Shitara, Y., Lu, C., Li, A. P., Y. Kato, Y., Suzuki, H., Ito, K., Itoh, T., Sugiyama, Y., Cryopreserved human hepatocytes as a tool for the prediction of in vivo transport and transporter-mediated drug-drug interactions, Abstract of International Conference on Drug Interaction, Hamamatsu, October 21-23, 1999, p. 87. 

The expression of a significant gut wall first-pass extraction ratio has several implications for affected drugs. First, oral bioavailability is lower than would be expected from the extent of absorption and the hepatic first-pass extraction. Second, the variability in expression of gut wall metabolic enzymes and transporters can lead to significant variability in gut wall first-pass extraction and thus oral bioavailability. Finally, the site of expression of these enzymes and transporters (i.e., the villus tip) brings them into contact with potentially co-administered drugs or dietary constituents, which could be inhibitors or inducers. Thus, there is the potential for drug-drug interactions at the level of the gut wall. 

As a general rule, when two drugs are co-administered the compound with the higher potential to form H-bonds with the transporter inhibits or reverses the transport of the compound with the lower potential to form H-bonds, provided that the membrane concentration of compounds are comparable (e.g., Km). This phenomenon tends also to dominate drug-drug interactions related to P-gp, and is demonstrated in Figs. 20.11 and 20.13. 

Romsicki, Y., Sharom, F. J., The membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter, Biochemistry 1999, 38, 6887-6896. 

The answer is d. (Kai ung, p 505.) Fluoxetine is a highly selective serotonin re uptake inhibitor (55RI) acting on the 5-1 IT transporter. It forms an active metabolite that is effective for several days. Selective serotonin reuptake inhibitors are inhibitors of cytochrome P450 isoenzymes, which is the basis of potential drug-drug interactions... 

A potential drug-drug interaction has also been described for the combination of gemfibrozil with several statins. Studies in healthy volunteers have demonstrated that gemfibrozil increased the AUC and Cm ix of rosuvastatin by 1.9- and 2.2-fold, respectively [43]. These results could be confirmed in vitro using Xenopus oocytes. In these experiments, gemfibrozil inhibited OATPIBl-mediated rosuvastatin transport... 

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