Elsevier

Drug Discovery Today

Volume 6, Issue 16, 15 August 2001, Pages 835-839
Drug Discovery Today

Review
Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy

https://doi.org/10.1016/S1359-6446(01)01892-XGet rights and content

Abstract

The blood- and tissue-concentrations, and thus the activity, of many drugs are influenced by factors that are subject to inter-individual variation. Variables that influence blood levels are metabolizing enzymes and transporters. Transporters control drug uptake, distribution and elimination. Transport by efflux pumps such as MDR1-encoded P-glycoprotein can influence the bioavailability of drugs. Knowledge of the transporter ‘status’ might allow for compensation of differences in drug uptake, such as by dose adjustment, which is important for drugs with narrow therapeutic windows. So far, intestinal expression of MDR1 has been determined by cumbersome methods, such as biopsies, although recently a functional polymorphism has been identified, which discriminates individual high or low-expressor alleles. As a result, clinical trials and therapy can be adapted to the ‘MDR1-status’ of individual patients.

Section snippets

MDR1 gene

The MDR1 gene was initially discovered as the precursor to a protein associated with a major problem of cancer chemotherapy: failure caused by cross-resistance of tumors to many different cytotoxic agents. This phenotype, confirmed by experimental analyses in vitro (over-expression of MDR1 causes resistance in cultured tumor cells), is shared by other members of the transporter family that are closely related to MDR1 (multidrug resistance associated genes, MRP1-5, Refs 1, 2, 3, 4, 5, 6, 7, 8, 9

MDR1-encoded Pgp – a bioavailability gene

Despite the high expression of Pgp in many cancers, where it poses a severe problem because it mediates cells that are resistant towards many chemotherapeutic agents, the physiological function of Pgp is not restricted to tumors. MDR1 is expressed in many normal tissues. One physiological function of Pgp could be in the adrenal cortex and might involve the metabolism of steroids 20. In other tissues, Pgp acts as a cellular efflux pump to control the intracellular concentration of substances.

Variability and polymorphisms in the human MDR1-gene

The current model of the SAR of Pgp and its mode of action is that two homologous halves, each with six transmembrane domains and one ABC-domain, recognize substrates, interact with each other and use energy (ATP) for transport. This is the result of the analyses of many variant Pgp molecules that have been recombinantly produced. Using these recombinant technologies, it has become clear that substrate specificity is affected by mutations in TMDs 5, 6, 11 and 12. This indicates the presence of

Pharmacological implications of transporter pharmacogenetics

Absorption, distribution, metabolism and elimination are major factors that affect the therapeutic efficacy of compounds. Pgp and other ABC transporters are proven to play a role in these processes, by providing a barrier to entry of compounds into the body, as well as controlling their rate of transfer between different tissues and compartments. The discovery of genetic variations that influence the function or expression of Pgp can have a direct impact on the likelihood of intestinal

Conclusions

Genetic variability and functional polymorphisms in ABC transporters are relevant pharmacological factors that have to be considered together with drug-metabolizing enzymes, whose activity show a large degree of inter-individual variability 55. Therefore, combined analyses of the variable activity of metabolizing enzymes and of transporter polymorphisms can be used to understand the individual variability in drug response. This will not only be of advantage for the development of novel drugs

Acknowledgements

Part of this work is supported by grant no. 01GG9846 from the German Ministry for Education and Research.

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