Drug-transporter interactions

These values were obtained from the University of Washington s Metabolism and Transport Drug Interaction Database http //www.druginteractioninfo.org rfOgilvie et al. (217). 

Metabolism and Transport Drug Interaction Database A Web-Based Research and Analysis Tool... 

Figure 2 List of precipitants evaluated with the substrates bupropion and efavirenz and which have shown more than 20% effect in in vivo inhibition. Display from the Metabolism and Transport Drug Interaction Database (http //www.druginteractioninfo...

Metabolism and transport drug interaction database. http //depts. washington.edu/didbase (accessed 2003 Mar 24). 

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). 

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. 

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