3.3.1 Gene Polymorphisms and Their Implications in Diseases
Genetic polymorphism of drug transporters is a potential determinant of interindividual variability in drug absorption, disposition, and elimination. The coding region polymorphism can be classified as synonymous variants, which do not cause amino acid changes, and nonsynonymous variants, which do cause amino acid changes. The difference in the specific genotype, age, ethnicity, and sex of the patients may contribute to the variants in genetic polymorphisms. In most cases, polymorphism arises from people of different ethnic origins and/or reflects acquired changes during infancy. Nonsynonymous variants can lead to completely altered transporter functions or partially modified transporter functions. Sometimes, such variants have no effects on functions. Those variants causing dramatic functional change have been targets of major studies. Transporters in liver, kidney, intestine, and brain are the greatest source of variability, which results in different drug disposition profiles. Thus the consequences of polymorphism of these transporters have received considerable attention in recent clinical studies or personalized drug therapy researches.
The multidrug resistance associated protein MRP2 belongs to the ATP binding cassette (ABC) family of transporter proteins, which mediate ATP dependent transfer of solutes. As an important canalicu-lar transport protein, MRP2 is responsible for the hepatic excretion of drugs-metabolites. A mutation on the MRP2 gene at codon 1066 from CGA to TGA, which changes arginine to stop-codon, has been proven to cause the rare autosomal recessive liver disorder, Dubin-Johnson syndrome (DJS) in humans.37 Patients with DJS have chronic conjugated hyperbilirubinemia caused by impaired hepatobiliary transport of nonbile salt organic anions.
Another important canalicular transport protein for drugs-metabolites, the bile salt export pump BSEP, is involved in progressive familial cholestasis (PFIC-2) in a subgroup of infants and children. The disease is characterized as a cholestatic disorder causing extreme pruritus, growth failure, and can progress to cirrhosis in the first decade of life.38 Mutations on the BSEP gene, such as 890A ^ G (E297G) and 2944G ^ A (G982R), result in a dysfunction of the transport protein, which is characterized by impaired active transport of bile acids across the hepatocyte canalicular membrane into bile.
Organic anion transporters are a family of transporters expressed in multiple organs. Due to their ability to transport a large number of the most commonly prescribed drugs, they played a critical role in maintaining endogenous homeostasis, are implicated in several clinical disorders, and are important modulators of drug efficacy and toxicity.3 9 Urate transporter 1 (URAT1) is a member of the organic anion transporter family. Studies showed that URAT1 was involved in the hereditary disease renal hypouricemia. This disease is more prevalent in
Japanese and non-Ashkenzai Jews than in other ethnic groups. Patients with this disease have low serum urate levels. They have no renal or systemic diseases except for the development of nephrolithiasis or exercise-induced acute renal failure. Some patients with this disease have defects in URAT1.40-42 The most frequently found mutation W258Stop of URAT1 results in a premature truncated protein, which is devoid of the transporter function due to deficiency in targeting to cell membrane.i0 Several studies have demonstrated that the single i nucleotide polymorphisms (SNPs) or regulatory SNP ( rSNPs) sometimes could result in interindividual variation in mRNA expression of OATs and could potentially regulate the drug PKs in human tissues or animal models.43-45 However, some conflicting data on the effects of polymorphisms on the function of drug transporters such as OAT3 or OAT1 may highlight that some SNP might be substrate or race specific.
As one important member of the ABC superfamily, Pgp has been one of the most studied membrane transporter proteins. Overexpression of Pgp is involved in multidrug resistance (MDR) in canceré6-48 Due to the fact that Pgp is responsible for protecting tissues and organs from toxicants, its malfunction may contribute to the progression of various diseases. It has been reported that patients with ulcerative colitis have a higher frequency of the nonsynonymous polymorphism of Pgp (C3435T genotype), which results in a decreased expression of Pgp in the intestine.49
3.3.2 The Involvement of Drug Transporters in Other Diseases
Recently studies showed that the development of some pathophysio-logical conditions was accompanied by the redistribution of OAT1 or OAT3 from cell membrane to intracellular compartments. In a rat model with bilateral ureteral obstruction (BUO), a disease characterized by the development of hemodynamic and tubular lesions, a redistribution of rOAT1 from cell membrane to intracellular compartments was found and contributed to the down-regulation of rOATl mediated PAH uptake.i0 During the progress of BUO, the expression level of angiotensin II (Ang II) is elevated. It was shown that treatment of Ang II in COS-7 cells could down-regulate the function of hOATl by decreasing its surface expression,51 which indicates that the altered function of OATs regulated by Ang II may be potentially responsible for the abnormal drug elimination found in BUO patients.
Another example of the involvement of OATs in the progression of diseases is acute renal failure (ARF), which is a clinical condition contributed to >50% of mortality rate.52 Both mRNA and protein level of OAT1 and OAT3 was revealed to be down-regulated in ischemic acute renal failure (iARF) rats, which might contribute to the impaired secretion of PAH found in iARF.53,54 Organic anion transporters play an important role in the renal drug clearance, the functional inhibition of OAT1 and OAT3 would likely have a substantial impact in the renal retention and elimination of organic anions in iARF patients.
There are various drug transporters expressed in the brain, which are responsible for the complex transport system of xenobiotics into the brain. Altered expression of drug efflux transporters at the blood-brain barriers and in brain parenchyma is related to many central nervous system (CNS) diseases. For example, a large number of studies have shown the correlation between polymorphisms of Pgp and diseases, such as pharmacoresistant epilepsy,5,56 and Parkinson's disease.57-59 On the other hand, as a feedback, neurological diseases and pathological conditions of the CNS may also lead to altered expression of functional drug transporters, which leads to increased complexity of related CNS diseases and refractory to therapy.
Since many drug transporters can accept multiple drugs and/or xenobiotics as substrates, there is a high likelihood that coadministra-tion of drugs and/or xenobiotics can competitively inhibit each other's transport. This may result in drug-drug interactions at the transport level.60
Organic anion transporters are important transporters involved with renal drug elimination. Coadministration of their substrates can lead to different pharmacokinetics of each drug due to modified transport. A notable example is the coadministration of an OAT substrate, the anti-cancer drug methotrexate, with OAT inhibitors/substrates including non - steroidal anti - inflammatory drugs (NSAIDs), penicillins, and probenecid. Such coadministration leads to diminished transport of methotrexate by OAT and can lead to altered drug concentrations with undesirable pharmacological consequences. For example, coadminis-tration of methotrexate with probenecid, an OAT inhibitor, resulted in severe suppression of bone marrow through inhibition of the tubular secretion of methotrexate.61
The breast cancer resistance protein BCRP also belongs to the ABC transporter family. The BCRP protein can reduce the intracellular concentration of potential harmful substances through efflux. At the same time, it also can cause drug resistance by eliminating useful drugs from cells. Coadministration of topotecan, a BCPR substrate, with elacridar (GF120918), a BCRP/Pgp inhibitor, significantly increases the oral bioavailability of topotecan in animal model studies.62 The same phenomenon has also been observed in a recent clinical study in cancer patients.63 In another study, coadministration of GF120918 (an inhibitor for both BCRP and Pgp) with a potent antagonist of the N-methyl-d-aspartate receptor, GV196771, for the treatment of neuropathic pain can increase the bioavailability of GV196771.64 Overall, coadministration of BCRP substrates and its inhibitor has been shown to result in drug-drug interactions due to modified transport capabilities. These data also clearly indicated that drug transporter plays an important role governing the absorption of substrate molecules.
Other examples of drug-drug interactions at the transport level involve the organic cation/carnitine transporters (OCTNs). It has been reported that competition between cephaloridine (P-lactam antibiotic) and carnitine transport at the level of OCTN2 can lead to renal mito-chondrial damaged5,66 In another study, the plasma concentration of sulpiride (a dopamine D2 receptor antagonist) decreased after concomitant oral administration with OCTN1 and OCTN2 substrates and/ or inhibitors in rats.67 Considering its wide tissue distribution in liver, intestine, kidney, brain, heart, and placenta, drug-drug interactions involving OCTNs can have broad impacts on the reabsorption, distribution, and elimination of their substrates and have profound clinical implications in our daily life.
The effect of drug transporter-related drug-drug interactions on bioavailability, tissue distribution, and pharmacological or toxico-logical functions of drugs can lead to altered therapeutic efficacy, unexpected adverse effects, and even toxicity. Understanding the interaction of the drug molecule with drug transporters, and the consequences of coadministration of multiple drugs has tremendous clinical implications.
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