Genetic Variability In Drug Transporters And Adverse Drug Reactions

Transport proteins that actively mediate the influx and efflux of drugs across cell membranes have an important role in regulating the absorption, distribution, and excretion of many medicines. Many different influx and efflux transporters have now been described (90), and polymorphisms have been described in many of the genes encoding for these proteins (91,92). In general, an efflux pump may mediate toxicity via the following possible pathways:

• Reduced activity of the efflux pump may increase the oral bioavailabilty of the drug and reduce renal and biliary excretion leading to increased plasma levels for a given dose and possible dose-dependent adverse effects. Overactivity would thus have the opposite effect and may lead to the need for increased dosage requirements.

• Reduced activity at the level of the cell membrane may increase intracellular levels because of reduced efflux and lead to toxicity of drugs, where the mode of toxicity depends on intracellular accumulation, for example, anti-cancer agents.

Influx pumps and variability in their activities would have effects opposite of those outlined here but have not been adequately studied.

The most extensively studied of the transporters is P-glycoprotein, a member of the adenosine triphosphate (ATP) binding cassette family, which is encoded by the human MDR1 (or ABCB1) gene. Many drugs including anticancer drugs, cardiac glycosides, immunosuppressive agents, glucocorticoids, and antiretrovirals are known substrates for MDR1 (93-95). A single nucleotide polymorphism (C3435T) in exon 26 of the MDR1 gene has attracted most attention, although subsequent studies have produced contradictory results as to the effects of this polymorphism on both the function of the transporter and its association with disease (96,97). This may be a reflection of the complicated pattern of linkage disequilibrium within this gene, and its variability in individuals of different ethnicity (98-100). Various ADRs have been related to this and other polymorphisms within the MDR1 gene (Table 3), but none of these studies have been replicated, and the true significance of the findings remains unclear, given the uncertain functional nature of the polymorphisms.

Table 3 Adverse Drug Reactions Associated with Polymorphisms in the MDR1 Gene

Drug

Adverse reaction

Nortryptiline

Hypotension

Tacrolimus

Neurotoxicity

Cyclosporin

Cyclosporin toxicity

Ivermectin

Neurotoxicity

Digoxin

Digoxin toxicity

Phenytoin

Phenytoin toxicity

Indinavir

Insulin resistance

There have been few studies with regard to the other transporters, but this reflects an important area of research that is likely to uncover novel mechanisms of ADRs. For instance, mutations have been identified in the photoreceptor-specific ATP-binding cassette transporter gene (ABCA4) in patients with Stargardt disease and age-related macular degeneration, both of which are disorders of the retinal pigment epithelium and neural retina. Because of certain phenotypic similarities between these disorders and 4-aminoquinoline (chloroquine and hydroxychloroquine)-induced retinopathy, a disorder where the mechanism is unclear, Shroyer et al. (101) were able to show that in eight patients with retinopathy, two had ABCA4missense mutations while three others had missense polymorphisms. This clearly does need to be investigated in a larger number of patients, but nevertheless, these preliminary findings provide some insight into the possible pathogenesis and genetic predisposition.

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