Association between CYP3A4/CYP3A5 genetic polymorphisms and treatment outcomes of atorvastatin worldwide: is there enough research on the Egyptian population?

A review article showed that atorvastatin and several statins' metabolic pathways depend on CYP3A4. Therefore, any mutation in this gene could result in a significant alteration in the PK of these statins [24]. The outcome of Maekawa et al. in vitro study illustrated that CYP3A4*16 variant found in East Asia had more than 60% decreased functional activity for atorvastatin. Furthermore, the study concluded that the clinical significance of the results should be examined in other prospective studies [29]. In this context, Jani et al. reported that a genetic mutation in CYP3A4 can result in variation in the pharmacologic properties of statins like atorvastatin. The study found that genetic variations in CYP3A4 gene influenced CYP3A4 enzyme activity and affected atorvastatin metabolism in 125 Indian subjects in Gujarat [30].

Increase in serum HDL-C level: Genetic mutations in CYP3A4 and other five genes affected the therapeutic efficacy of atorvastatin in Indians, suffering from coronary artery disease. Poduri et al. reported CYP3A4 allele (189F/S) was linked to elevated high-density lipoprotein cholesterol (HDL-C) levels after atorvastatin therapy (P<0.05) [31].

Decrease in serum total cholesterol: Moreover, Gao et al. found that the decline of total cholesterol (TC) serum level was related to CYP3A4*1G mutation in Chinese subjects with hyperlipidemia. The mean percentage decrease in serum TC level was 20.9±5.0% (*1G/*1G), 17.8±3.8% (*1/*1G), and 16.8±3.3% (*1/*1), respectively (P<0.01). Therefore, this genetic polymorphism in CYP3A4 increased the efficacy of atorvastatin therapy [32].

Decrease in serum LDL-C level: Peng et al. reported that a single nucleotide polymorphism (SNP) of CYP3A4, rs2242480, was associated with a reduction in serum LDL-C level among Chinese patients with ischemic stroke (P = 0.049) [33]. In this context, Kajinami et al. reported that M445T variant of CYP3A4 gene was associated with a significantly lower pretreatment serum LDL-C levels (11.2%) in carriers of this variant relative to non-carriers. In addition, in the M445T allele carriers, a higher LDL-C lowering response to atorvastatin was detected among 340 Americans suffering from primary hypercholesterolemia, although it failed to reach statistical significance [24, 34].

Improvement in serum lipid and lipoprotein levels: Furthermore, Alexy Rosales, et al. studied Chilean patients and revealed that CYP3A4*1B (-290A>G, rs2740574) was linked to enhanced therapeutic outcomes after four weeks of atorvastatin pharmacological treatment. This variant led to a substantial reduction in TC and LDL-C with a significant increase in HDL-C. The mean percentage change in serum TC was − 16.1±9.1% (A/A), and − 24.4±11.8% (A/G), respectively (P<0.001). For serum LDL-C, it was − 22.2±13.5% (A/A), and − 36.4±17.8% (A/G), respectively (P<0.001). In addition, for serum HDL-C, it was 14.9±13.0% (A/A), and 31.8±16.1% (A/G), respectively (P<0.001) [21].

Increase in serum LDL-C level: From the same perspective, CYP3A4 genetic polymorphisms could decrease the pharmacological effect of atorvastatin. For example, Kajinami et al. showed that after 52 weeks of atorvastatin therapy (10 mg/day), the A-290G mutant allele of CYP3A4 (CYP3A4*1B) was related to increased levels of LDL-C in 340 American subjects with hypercholesterolemia (P<0.05) [24, 34, 35].

Less serum LDL-C level decline: After 8 weeks of atorvastatin treatment (10 mg/day) among 177 Indians, Kadam et al. illustrated that the variant-allele of CYP3A4 rs2740574 was associated with a lower LDL-C serum level reductions than the wild-type allele (P<0.05) [36].

Decrease in AUC_0–∞: Klein et al. studied 56 Finnish subjects and analyzed atorvastatin and its dominant metabolite 2-OH-atorvastatin (CYP3A4-dependent) concerning specific SNPs. The results demonstrated that CYP3A4*22, the T variant of the SNP rs35599367, was associated with a decrease in 2-OH-atorvastatin/atorvastatin area under the plasma concentration-time curve (AUC0–∞) ratio (P<0.001). This study concluded that SNP rs35599367 (CYP3A4*22) could imply variation in response to atorvastatin and other CYP3A4 substrates [37]. Moreover, He et al. illustrated that the CYP3A4*1G variant affects atorvastatin and 2-OH-atorvastatin PK in 20 Han Chinese subjects with coronary artery disease. CYP3A4*1G/*1G genotype was associated with less AUC0–∞ for both atorvastatin and 2-OH-atorvastatin than *1/*1 or the *1/*1G genotypes (P<0.05) [27].

Carriers of at least a copy of CYP3A5*1 allele (wild-type) express CYP3A5 protein, whereas CYP3A5*3 homozygotes are designated as CYP3A5 non-expressors [25]. A study reported the genotype frequency of the CYP3A5 genetic variations in 350 unrelated Greek Caucasian cases with primary hypercholesterolemia: 13.4% for expressors and 86.6% for non-expressors (homozygous) subjects [38]. CYP3A5 enzyme is not expressed in about 90% of Caucasians [25].

Improvement in serum lipid and lipoprotein levels: CYP3A5*3 allele led to an improvement in response to atorvastatin. Kari T. Kivistö et al. studied 46 Europeans (Caucasian subjects) and revealed that atorvastatin was significantly less effective in the carriers of CYP3A5*1 (expressors) than in the carriers of CYP3A5*3 (non-expressors). After 12 months of treatment, the mean serum TC and LDL-C levels were higher in the expressors of CYP3A5 (P<0.05) [24, 25, 35]. Moreover, Genovefa Kolovou et al. revealed that LDL-C, TC, and triglyceride (TG) serum levels were decreased significantly after atorvastatin treatment in 175 Greek carriers of both CYP3A5*3/*3 and CYP3A5*1/*3 genotypes (P<0.05) [38].

Decline in response to atorvastatin: A review by Dagli‑Hernandez et al. about clinical trials in Brazilians showed that variations in the CYP3A5 gene were associated with a reduction in response to atorvastatin and simvastatin therapy [15]. In the same context, a Brazilian study involving 139 subjects illustrated that the CYP3A5*3A variant (*1D and *3C combined variants) was linked to a decrease in cholesterol-lowering response to atorvastatin-4 weeks therapy in non-African subjects only. In this study, 93 subjects with non-African ancestry were recruited, and the remaining 46 individuals were Africans [35, 39]. Non-Africans carrying the CYP3A5*3C allele (*3C/*3C genotype) had less decline in serum TC and LDL-C than carriers of CYP3A5*1A allele after atorvastatin treatment (P<0.05). In addition, the CYP3A5*1D analysis illustrated that for the *1D variant (*1D/*1D genotype) among non-Africans, carriers had less reduction of TC and LDL-C levels than carriers of CYP3A5*1A allele after atorvastatin treatment (P<0.05) [39].

A review by Vrablik et al. indicated that mutant alleles within CYP3A4 have been proposed to be linked to myopathy as an adverse effect of stains. Moreover, CYP3A4 has been indirectly associated with myopathy in atorvastatin users due to its overrepresentation in these patients needing dose reduction or switching from atorvastatin to alternatives [40, 41]. Furthermore, Xia et al. screened 187 Chinese subjects for wild alleles CYP3A4*1B (rs2740574) and CYP3A4*1G (rs2242480) in addition to other genes involved in atorvastatin metabolism and transport in vivo. However, only six candidates were enrolled to study atorvastatin PK. As a result, atorvastatin's maximum plasma concentration (Cmax) was significantly elevated (high atorvastatin exposure). In addition, one subject of the candidates was terminated during the study due to atorvastatin intolerance [42]. However, according to Becker et al. cohort study, the G allele of CYP3A4*1B in Dutch users of atorvastatin or simvastatin was linked to a reduced risk for statin intolerance, specifically among females and carriers of the mutant allele (3435T) of the transporter ABCB1 [41].

Liu et al. in vitro study showed that atorvastatin metabolism is decreased and significantly associated with CYP3A5*3. In addition, the two atorvastatin metabolites, para-OH-atorvastatin and ortho-OH-atorvastatin, were significantly reduced in carriers of CYP3A5*3/*3 [43]. This finding was consistent with severe muscle damage associated with CYP3A5*3/*3 [43, 44]. Wilke et al. conducted an American retrospective case-control study on 137 Caucasian subjects with European ancestry. It showed that the CYP3A5*3 variant was allied to the increase in the serum level of creatine kinase (CK) in the case of individuals with myalgia. The study concluded that individuals with myalgia while using atorvastatin were at a high risk of developing a severe myopathy if they were carriers of the CYP3A5*3/*3 genotype (P<0.05) [44, 45]. Also, the previously mentioned Chinese study on atorvastatin PK by Xia et al. illustrated the significant elevation in atorvastatin Cmax. This risky elevation was also associated with the allele CYP3A5*3(rs776746) in addition to the previously stated genes for atorvastatin metabolism and other two genes for atorvastatin transport: solute carrier organic anion (SLCO) transporter; (SLCO1B1 388A>G (rs2306283) and SLCO1B1 521T>C(rs4149056)) [42]. Quite the opposite, a Spanish pharmacogenetic study by Zubiaur et al. on 156 subjects (81 Caucasians, 70 Latin Americans, and 5 Blacks or Arabs) showed that atorvastatin accumulation was higher among CYP3A5*1/*1 carriers than *1/*3 or *3/*3 carriers. The authors justified this novel finding by illustrating the first-pass effect on the administered acid form of atorvastatin. Therefore, regarding the CYP3A5*1/*1 genotype, atorvastatin was metabolized to a greater extent in the gut. This genotype resulted in active metabolites and inhibitors of CYP3A4 (responsible mainly for atorvastatin metabolism). Consequently, CYP3A5*3 variant was significantly linked to lower atorvastatin Cmax than CYP3A5*1 (p = 0.018) [26].