DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.

To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.

We have shown that CYP2B6 genetic polymorphism markedly influences the metabolism of efavirenz in human liver microsomes. Importantly, the CYP2B6*6 allele harboring the SNPs c.516G>T [Q172H] and c.785A>G [K262R] was significantly associated with a pronounced decrease in CYP2B6 expression and activity, as well as a low rate of efavirenz 8-hydroxylation. These results represent a first step towards elucidating the mechanism by which this allele identifies patients exhibiting very high efavirenz plasma concentrations.

Polymorphisms in drug-metabolizing enzymes and drug transporters contribute to wide and inheritable variability in drug pharmacokinetics, response and toxicity. One of the less well-studied human cytochrome P450s is (CYP)2B6, a homologue of the rodent phenobarbital-inducible CYP2B enzymes. Clinically used drug substrates include cytostatics (cyclophosphamide), HIV drugs (efavirenz and nevirapine), antidepressants (bupropion), antimalarials (artemisinin), anesthetics (propofol) and synthetic opioids (methadone). Contrary to the model polymorphisms of CYP2D6 and CYP2C19, which were discovered by adverse drug reactions, pharmacogenetic study of CYP2B6 was initiated by reverse genetics approaches and subsequent functional and clinical studies. With over 100 described SNPs, numerous complex haplotypes and distinct ethnic frequencies, CYP2B6 is one of the most polymorphic CYP genes in humans. In this review, we summarize general biomolecular and pharmacological features and present a detailed up-to-date description of genetic polymorphisms, including a discussion of recent clinical applications of CYP2B6 pharmacogenetics.