Transporters, drug molecular mechanism

As SNP discovery technologies become mainstream research tools, the importance of genotype-phenotype relationships will continue to be a focus in pharma-cogenomic research. Not only will characterization of drug transporter polymorphisms enhance our insight of the molecular mechanisms involved in transporter function, it is likely that such findings will become important components of individualized drug therapy in the future. 

Groneberg DA, Fischer A, Chung KF, Daniel H (2004) Molecular mechanisms of pulmonary peptidomimetic drug and peptide transport. Am J Respir Cell Mol Biol 30(3) 251-260. 

Transporter-Mediated Drug Interactions Molecular Mechanisms and Clinical Implications... 

As mentioned earlier, the underlying mechanisms for many of the transporter-mediated interactions are not fully understood and remain elusive at the present time. With the limited knowledge on the molecular mechanisms of transporter-mediated interaction and the fact that many inhibitors and inducers can simultaneously affect both drug transporters and CYP enzymes, it is difficult to quantitatively differentiate transporter-mediated interactions from CYP-mediated interactions. From the literature, it becomes clear that evidence of transporter-mediated dmg interactions, with few exceptions, is often indirectly derived from in vitro transport studies with cellular culture models and heterologous expression systems. 

H. Harder, then in our laboratory but now at George Washington University, was responsible for these studies. He also checked that the synthesis of precursor molecules for DNA, and the transport of these across membranes was not responsible for the inhibition. He has more recently shown that the ability of the DNA to act as a template for new synthesis is strongly inhibited by the platinum drug. These results can be most reasonably explained by the hypothesis that the anticancer activity of the platinum drugs arises from a primary attack on DNA. The battle to discover the molecular mechanism of action was, therefore, joined on the field of metal complex interactions with DNA, and numerous other laboratories entered the fray. The booty has been rich, embarrasingly so. 

Fig. 7 Possible model for the molecular mechanism of multidrug transporters. MDR1-P-glycoprotein (substrates are recognized in, or near to the membrane lipid phase). Abbreviations hD hydrophobic drugs, PL Phospholipids. (Reproduced from [4])...

Masuda S, Inui K. [Molecular mechanisms on drug transporters in the drug absorption and disposition] Nippon Rinsho 2002 60(l) 65-73. 

MOLECULAR MECHANISM OF PXR- AND CAR-DEPENDENT DRUG TRANSPORTER REGULATION... 

Pharmacology, the study of agents and their actions, can be divided into two branches. Pharmacodynamics is concerned with the effects of a drug on the body and, therefore, encompasses dose-response relationships as well as the molecular mechanisms of drug activity. Pharmacokinetics, on the other hand, is concerned with the effect of the body on the drug. Drug metabolism, transport, absorption, and elimination are components of pharmacokinetic analysis. 

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