DILI [34, 36]. However, it has been suggested that BSEP inhibition alone might not be a good predictor of DILI risk [37] as drugs inhibiting the BSEP often inhibit other transporters as well, and it may be the cumulative effect that causes toxic bile acid accumulation [38]. In support of this theory, hepatoxicity induced by isoniazid and rifampicin may be due to the inhibition of both NTCP and BSEP [39]. Additionally, the discontinued HER2 tyrosine kinase inhibitor CP‐724,714 inhibits efflux transporters BSEP and MDR1, which contributes to the toxic accumulation of drug and bile acids [40].
2.5 Genetic Variants and Their Impact for Pharmacokinetic Behavior and Safety
Genetic variation can result in decreased, unchanged, or increased enzymatic function [41, 42], and therefore could significantly impact drug safety by altering pharmacokinetic characteristics in certain individuals [43]. Based on decades of pharmacogenetic research, the association between genetic variation and drug metabolism has been established for many drugs [44]. The FDA has published a list of pharmacogenetic associations with sufficient scientific evidence [45]. However, often contradictory evidence for a given drug is reported, usually due to the limited statistical power in many studies. This is of particular importance in establishing associations between genotypes and DILI, as DILI has a very low incidence (~20 per 100 000 inhabitants annually) and clinical diagnosis is challenging [46]. The association between genotype and hepatotoxicity has been suggested for CYP2C9‐Bosentan, NAT2‐isoniazid and others (Table 2.2).
Table 2.2 Selected reports for the association between gene variations and drug‐induced liver injury.
| Gene | Variant | Function | Affected subgroups | Drug | DILI risk association | References |
|---|---|---|---|---|---|---|
| CYP2B6 | *1H and *1J (‐2320T>C) | Increased expression | Ultrarapid metabolizers | Ticlopidine | Increased risk | [47] |
| CYP2B6 | *6 | Decreased function | Poor metabolizers | Efavirenz | Increased risk | [48] |
| CYP2C9 | *2 | Decreased function | Poor metabolizers | Bosentan | Increased risk | [49, 50] |
| CYP2E1 | c1/c1 | Increased expression | Ultrarapid metabolizers | Isoniazid | Increased risk | [51] |
| NAT2 | *4 | Without active alleles | Slow acetylators | Isoniazid | Increased risk | [51–53] |
| UGT1A6 | A528G | Silent mutation | Tolcapone | Increased risk | [54] | |
| UGT2B7 | *2 | Decreased function | Poor metabolizers | Diclofenac | Increased risk | [55, 56] |
| GSTM1 and GSTT1 | Double null genotype | Decreased function | Poor metabolizers | Troglitazone | Increased risk | [57] |
| ABCB1 | 3435C>T | Decreased expression | Nevirapine | Decreased risk | [58, 59] | |
| ABCB11 | D676Y, G885R and V444A | Decreased function | Ethinylestradiol/gestodene | Increased risk | [60] | |
| ABCC2 | C‐24T | Decreased expression | Diclofenac | Increased risk | [55] | |
| ABCC2 | C‐24T | Decreased expression | Deferasirox | Increased risk | [61] |
For the major CYPs the single nucleotide polymorphism (SNP) has been estimated to be 14–127 per kilobase pair [62]. Of these SNPs, 9–41% are nonsynonymous variants. Only a limited number of SNPs (6–30%) have been cataloged or functionally annotated by the Pharmacogene Variation (PharmVar) Consortium, a public central repository for pharmacogene (PGx) variation (www.pharmvar.org). In addition to SNPs, variations such as insertions and deletions are present. The polymorphism phenotype can be categorized into four types; i.e. poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra rapid metabolizer. Poor metabolizer usually refers to individuals carrying homozygous or compound heterozygous null alleles (no function). In intermediate metabolizers one allele is partially defective while the other either is partially defective or null. For extensive metabolizers at least one allele is fully functional. Individuals with gain‐of‐function polymorphisms, e.g. carrying extra gene copies and mutations that enhance enzyme activity, belong to the ultra rapid metabolizer category.
2.5.1 CYP3A4
More than 34 SNPs of CYP3A4 have been included in the PharmVar, but generally they do not translate to significant interindividual variability [41, 42]. The observed variability could not be explained by the SNP variations in the coding and 5′‐flanking regions of CYP3A4 [63]. Instead, the variations that affect CYP3A4 expression are more relevant to drug metabolism. The cis genetic variant CYP3A4*22 has a 15389C>T substitution in intron 6, which results in decreased hepatic CYP3A4 expression. It has been suggested that CYP3A4*22 might be of clinical relevance to statin therapy, as the plasma concentration of the statin drugs (e.g. simvastatin and lovastatin) largely is dependent on CYP3A4 activity [64]. In a small cohort study the patients carrying a CYP3A4*22 allele required a significantly lower dose to reach target levels
