Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects

CYP2C9, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of 15–20% of clinically important drugs (warfarin, sulfonylureas, phenytoin, non-steroid anti-inflammatory drugs). To avoid adverse events and/or impaired drug-response, CYP2C9 pharmacogenetic testing is recommended. The impact of CYP2C9 polymorphic alleles (CYP2C9*2, CYP2C9*3) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C9*3 allele was associated with CYP2C9 functional impairment, and CYP2C9*2 influenced tolbutamide 4′-hydroxylase activity only in subjects with two polymorphic alleles, whereas the contribution of CYP2C8*3 was not confirmed. In addition to CYP2C9 genetic polymorphisms, non-genetic factors (co-medication with CYP2C9-specific inhibitors/inducers and non-specific factors including amoxicillin + clavulanic acid therapy or chronic alcohol consumption) contributed to the prediction of hepatic CYP2C9 activity; however, a CYP2C9 genotype–phenotype mismatch still existed in 32.6% of the subjects. Substantial variability in CYP2C9 mRNA levels, irrespective of CYP2C9 genotype, was demonstrated; however, CYP2C9 induction and non-specific non-genetic factors potentially resulting in liver injury appeared to modify CYP2C9 expression. In conclusion, complex implementation of CYP2C9 genotype and non-genetic factors for the most accurate estimation of hepatic CYP2C9 activity may improve efficiency and safety of medication with CYP2C9 substrate drugs in clinical practice.

AKR1D1*36 C>T (rs1872930) allelic variant is associated with variability of the CYP2C9 genotype predicted pharmacokinetics of ibuprofen enantiomers – a pilot study in healthy volunteers

The relative contribution of CYP2C9 allelic variants to the pharmacokinetics (PK) of ibuprofen (IBP) enantiomers has been studied extensively, but the potential clinical benefit of pharmacogenetically guided IBP treatment is not evident yet. The role of AKR1D1*36C>T (rs 1872930) allelic variant in interindividual variability of CYP450 mediated drug metabolism was recently elucidated. A total of 27 healthy male subjects, volunteers in IBP single-dose two-way cross-over bioequivalence studies were genotyped for CYP2C9*2, CYP2C9*3 and AKR1D1*36 polymorphisms. The correlation between CYP2C9 and AKR1D1 genetic profile and the PK parameters for S-(+) and R-(−)-IBP was evaluated. Remarkable changes in the PK values pointing to reduced CYP2C9 enzyme activity were detected only in the CYP2C9*2 allelic variant carriers. Statistically significant association between the AKR1D1*36 allele and the increased IBP metabolism (low AUC0-t and 0–∞, high Cltot and short tmax values for both enantiomers) was observed in subjects carrying the CYP2C9 *1/*3 or CYP2C9*1/*1 genotype. The clinical value of concomitant CYP2C9 and AKR1D1 genotyping has to be further verified.

Relevance of CYP2C9 Function in Valproate Therapy

Background: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient’s drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways. </P><P> Methods: CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions. </P><P> Results: The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype. Conclusion: Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients’ CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children’s anticonvulsant therapy.

Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease

Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t 1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.