Certain membrane-spanning proteins facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood–brain barrier, and drug uptake into target cells. Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action. P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism. P-glycoprotein is an energy-dependent transmembrane efflux pump encoded by the ABCB1 gene (also known as the multidrug resistance 1 gene), which is a member of the ATP-binding cassette (ABC) transporter superfamily. P-glycoprotein was first recognized for its ability to actively export anticancer agents from cancer cells and promote multidrug resistance to cancer chemotherapy. Later, it was discovered that P-glycoprotein is also widely distributed on normal cell types, including intestinal enterocytes, hepatocytes, renal proximal tubule cells, and endothelial cells lining the blood-brain barrier. At these locations, P-glycoprotein serves a protective role by transporting toxic substances or metabolites out of cells. P-glycoprotein also affects the distribution of some nonchemotherapeutic agents, including digoxin, the immunosuppressants cyclosporine and tacrolimus, and antiretroviral protease inhibitors (Fig. 9–3). Increased intestinal expression of P-glycoprotein can limit the absorption of P-glycoprotein substrates, thus reducing their bioavailability and preventing attainment of therapeutic plasma concentrations. Conversely, decreased P-glycoprotein expression may result in supratherapeutic plasma concentrations of relevant drugs and drug toxicity.
Sidebar: Clinical Controversy
Much of the data on individual variations in the ABCB1 gene and response to P-glycoprotein substrates are inconsistent and even conflicting and need to be clarified. Many drugs that are substrates for P-glycoprotein are also substrates for cytochrome P450 or other metabolizing enzymes. For example, cyclosporine is a P-glycoprotein and CYP3A4 substrate. Thus, ultimate drug concentrations and effects may be a consequence of both drug transporter and drug metabolizer genotypes.
At least 50 SNPs have been identified in the promoter and exon regions of the ABCB1 gene. The most commonly studied SNPs occur in exons 12 (C1236T), 21 (G2677T), and 26 (C3435T). These SNPs are in linkage disequilibrium (i.e., inherited together) and form several haplotypes. The exon 26 SNP appears to modify P-glycoprotein activity, and ABCB1 haplotype has been shown to alter substrate-binding specificity.64 Clinical studies have shown associations between ABCB1 SNPs and plasma digoxin concentrations.65 These data imply that the ABCB1 genotype may be useful in predicting digoxin concentrations in patients with atrial arrhythmias or heart failure and in choosing initial digoxin doses accordingly.
The ABCB1 genotype may also have important implications for drugs that need to reach the brain to exert their effects. In particular, increased ABCB1 expression may limit the ability of some antiepileptic agents to penetrate the blood brain barrier, thus leading to drug resistant epilepsy. Both phenytoin and phenobarbital are substrates for P-glycoprotein. There is evidence that the 3435CC genotype results in lower phenobarbital concentrations in the cerebral spinal fluid and a higher seizure frequency among patients taking phenobarbital for generalized epilepsy.66 Similarly, the 3435CC genotype has been associated with phenytoin-resistant epilepsy.66
Other examples of polymorphic drug transporter proteins include the organic anion transporter (OAT) and cation transporters, which are members of the solute carrier (SLC) transporter family. The SLC01B1 gene encodes for the OAT polypeptide B1, which mediates the uptake of HMG-CoA reductase inhibitors (statins) into the liver. While statins effectively lower total and low-density lipoprotein cholesterol and reduce the risk for cardiovascular events in coronary heart disease, their use is associated with an increased risk for myopathy (muscle pain or weakness with elevated creatine kinase levels), particularly with higher statin doses or concomitant drugs that increase statin bioavailability. Myopathy may rarely cause rhabdomyolysis, characterized by muscle breakdown and potentially leading to acute renal failure. A reduced function SLC01B1 SNP, resulting in a T to C substitution and designated as SLC01B1*5, has been associated with higher statin concentrations.67 Each copy of the C allele increased the risk for statin-induced myopathy by 4.5-fold in a recent case-control study.67
Similarly, the SLC01B1*5 allele, was associated with an increased incidence of less severe yet troubling adverse effects that lead to statin discontinuation, including myalgias without significant creatine kinase elevation.68 These data suggest that SLC01B1 genotyping may be useful in individualizing statin dosing, with lower doses and avoidance of medications that increase statin bioavailability in those with a reduced function SLCO1B1 allele to limit the risk for myopathy. Alternatively, the use of more lipophilic statins that can enter the liver via passive diffusion, and are not dependent on the OAT polypeptide B1, may be safer in carriers of a reduced function SLCO1B1 allele.