*6.2. Modulatory Effect of ABCG2 Variants on Drug Pharmacokinetics*

As discussed earlier, ABCG2 residing in various physiological barriers plays a pivotal role in tissue and cellular protection by controlling the uptake, distribution, and excretion of potentially toxic endogenous and exogenous substances. Mutations/polymorphisms affecting the functionality of the transporter by any means may also influence the serum level and/or the pharmacokinetic parameters of drugs that are ABCG2 substrates [96,158]. There are two consequences of altered pharmacokinetics: (i) the clinical response to a given drug can be modulated, and (ii) toxic reactions can arise due to shifted drug concentrations or drug–drug interactions. In particular, highly toxic drugs, like chemotherapeutic agents, can evoke adverse drug reaction (ADR) even at the usual dosage, when a polymorphism in transporters alters drug distribution. ABCG2 mutations/polymorphisms in connection with anti-cancer drug-elicited ADRs will be discussed in the following subsection. When drug concentrations (or exposures) are elevated due to the presence of a polymorphic variant, drug dosage should be adjusted accordingly to attain adequate response to treatment but to minimize side effects. However, compiling of dependable personalized treatment protocols demands not only reliable genetic analyses but also well-established knowledge of genotype–phenotype–pharmacokinetics relationships.

The effect of the frequent Q141K ABCG2 variant on drug pharmacokinetics has been extensively investigated, whereas only limited information has been acquired on other ABCG2 SNPs. Interestingly, the alterations in the disposition of several drugs correlate with the allele frequencies of this SNP in various ethnic groups [159]. Based on previous pharmacokinetic and pharmacodynamics data, a recommendation has been made to incorporate examination of ABCG2 Q141K in recent and future drug development [65]. Q141K has been demonstrated to modulate the pharmacokinetics of several types of drugs, including chemotherapeutic agents (discussed later), statins, disease-modifying anti-rheumatic drugs (DMARD), anticoagulants, and anti-viral medications. The pharmacokinetic pa-

rameters [the area under the curve (AUC) and/or the maximum concentration (Cmax)] of rosuvastatin, simvastatin, atorvastatin, and fluvastatin was elevated in patients carrying the Q141K allele [160–164]. Therefore, this polymorphism has also been implicated in increased the risk of statin-induced myopathy [165]. Q141K was also associated with higher AUC or Cmax of DMARDs, such as sulfasalazine and teriflunomide [166–169], as well as of anti-HIV drugs, such as dolutegravir and retegravir [170,171]. It is worth mentioning that in many cases, association was seen only with the homozygous genotype, or with the group involving both hetero- and homozygotes. With regard to the other relatively frequent polymorphisms, V12M has demonstrated not to influence the pharmacokinetics of fluvastatin [162], whereas Q126X was associated with altered disposition of sulfasalazine [169].

Interestingly, a few studies have reported that the polymorphism-related alterations in pharmacokinetic parameters were primarily due to increased intestinal absorption rather than decreased renal excretion [159,171], although reduced hepatic clearance may also contribute to lower Cmax values [166]. These notions are in concert with the differential pathology of Q141K in the intestine and the kidney observed in gout patients [58]. As discussed earlier, Q141K increases the risk of poor response to allopurinol by means of a not fully understood mechanism. However, further studies focusing on the oxypurinol pharmacokinetics and involving a large cohort of allopurinol-treated gout patients are needed to elucidate causative relationships.
