Effect Of CYP2C9 Polymorphisms Research Articles

A study on CYP2C9 polymorphism in Puerto Rican Alzheimer's Patients and its role in the Pharmacokinetics of ∆-9-tetrahydrocanna-binol

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects over 55 million people worldwide. Individuals with AD are often prescribed multiple medications to manage comorbidities, many of which are metabolized by enzymes from the cytochrome P450 (CYP). CYP2C9 is expressed by the CYP2C9 gene. The highly polymorphic gene is grouped into phenotypes such as poor, intermediate, normal, and ultra-rapid metabolizers that influence the pharmacokinetics (PK) of drugs and their metabolites. Among humans, CYP2C9 is one of the most essential enzymes for metabolizing drugs, including delta-9-tetrahydrocannabinol (THC). The enzyme converts THC into its active metabolite 11-hydroxy-delta-9-THC (OH-THC). IGC-AD1 is a formulation with two active pharmaceutical ingredients, delta-9-THC and melatonin. The Phase 1, multiple ascending dose (MAD) trial, was conducted on a Puerto Rican population. The participant population in the trial (N=13) was 69.2% female and 30.8% male, with an average age of 80.18 (SD+/- 6.22). We report on the effect of CYP2C9 polymorphisms on the pharmacokinetics (PK) of THC and its active metabolite in AD patients from a Phase 1 trial. Using a Mass ARRAY Analyzer 4 Instrument (Invitae Inc.), we determined the following CYP2C9 alleles: *2, *3, *4, *5, *6, *8, *11, *13, *15, and found that 60% of participants (N=6) were carriers of at least one polymorphism including 1*/2* and 1*/3*. The participants with intermediate metabolizers (*1/*3 and *1/*2) showed an increased half-life of THC and OH-THC with major differences between the two intermediate metabolizer groups *1/*3 and *1/*2. In the trial more females were noted to be intermediate metabolizers than males. As polymorphisms of CYP2C9 affect the PK of THC and its metabolite, larger studies are needed to establish PK baselines for polymorphisms of CYP2C9. In the meantime, it is recommended that researchers exercise caution while dosing AD patients with THC.

Pharmacogenetic Aspects of Type 2 Diabetes Treatment

In this article, we analyze the role of different variants of the KCNJ11, TCF7L2, SLC22A1, SLC22A3, CYP2C9, CYP2C8, PPARγ genes polymorphisms in efficacy of diabetes mellitus pharmacotherapy. T allele of the KCNJ11 rs2285676 gene polymorphism and G allele of KCNJ11 rs5218 gene polymorphism are associated with the response to IDPP-4 therapy; the presence of KCNJ11 gene rs5210 polymorphism A allele is a predictor of poor response. The effect of rs7903146 polymorphism of TCF7L2 gene was evaluated on the response to treatment of patients taking linagliptin. Linagliptin significantly reduced HbA1c levels for all three rs7903146 genotypes (CC: –0.82 %; CT: –0.77 %; TT: –0.57 %). A significantly smaller effect of therapy was observed with the genotype with ТТ. The rs622342 polymorphism of SLC22A1 gene was studied in effectiveness of metformin. The researches demonstrated that carriers of variant AA had an average decrease of HbA1c of 0.53 %, heterozygous – decrease of 0.32 %, and carriers of a minor variant of SS had an increase of 0.2 % in the level of HbA1c. A significant effect of CYP2C9 polymorphisms on the pharmacokinetic parameters of PSM was noted. When studying the kinetics of glibenclamide, it was found that carriage of the allele *2 significantly reduces glibenclamide metabolism: homozygous carriers had clearance 90 % lower than homozygous carriers of the wild variant. The studies confirmed the association of the allelic variants of Thr394Thr and Gly482Ser of PPARγ gene with higher efficacy of the rosiglitazone. The data obtained from the analysis of the association of the Pro12Ala polymorphism of PPARγ gene and the response to therapy is contradictory. Thus the personalized approach, based on the knowledge of polymorphism options, will allow choosing the most effective drug with transparent kinetics for each individual patient.

Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects.

Genetic polymorphisms in CYP2C9 account for 10-20% of the variability in warfarin dose requirement. As such CYP2C9 genetic polymorphisms are commonly included in algorithms aimed to optimize warfarin therapy as a way to account for variability in warfarin responsiveness that is due to altered pharmacokinetics. However, most of the currently available pharmacokinetic data were derived from studies among patients on chronic warfarin therapy and therefore suffer from the confounding effects of disease states and drug interactions. The purpose of the present study was to provide an accurate quantitative estimate of S-warfarin oral clearance (CLS) among healthy subjects carrying different CYP2C9 genotypes. Single dose of warfarin was administered to 150 non-smokers, age (mean±SD) 23.3±4.5years, 60% male, non-obese, healthy subjects. Blood samples were taken for up to 168h and urine was collected over the entire study period. Compared with carriers of the wild-type CYP2C9*1/*1 genotype (n=69), CLS was reduced by 25, 39 and 47% among heterozygote for CYP2C9*2 (n=41) CYP2C9*3 (n=26) and carriers of 2 variant alleles (n=14), respectively (p<0.001). The corresponding decrease in the formation clearance of 6 and 7 S-hydroxy-warfarin was 45, 65 and 75%, respectively (p<0.001). The current study provides an estimate concerning the effect of CYP2C9 polymorphisms on S-warfarin pharmacokinetics among healthy subjects. As such it is free of the confounding effects of disease states and drug interactions. Further research is needed to evaluate whether the incorporation of quantitative data obtained in the present study into pharmacogenetic warfarin algorithm may enhance its precision. Clinicaltrials.gov Identifier NCT00162474.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Comparative Pharmacokinetics of Vitamin K Antagonists

Vitamin K antagonists belong to the group of most frequently used drugs worldwide. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase. Each drug exists in two different enantiomeric forms and is administered orally as a racemate. The use of vitamin K antagonists is complicated by a narrow therapeutic index and an unpredictable dose-response relationship, giving rise to frequent bleeding complications or insufficient anticoagulation. These large dose response variations are markedly influenced by pharmacokinetic aspects that are determined by genetic, environmental and possibly other yet unknown factors. Previous knowledge in this regard principally referred to warfarin. Cytochrome P450 (CYP) 2C9 has clearly been established as the predominant catalyst responsible for the metabolism of its more potent S-enantiomer. More recently, CYP2C9 has also been reported to catalyse the hydroxylation of phenprocoumon and acenocoumarol. However, the relative importance of CYP2C9 for the clearance of each anticoagulant substantially differs. Overall, the CYP2C9 isoenzyme appears to be most important for the clearance of warfarin, followed by acenocoumarol and, lastly, phenprocoumon. The less important role of CYP2C9 for the clearance of phenprocoumon is due to the involvement of CYP3A4 as an additional catalyst of phenprocoumon hydroxylation and significant excretion of unchanged drug in bile and urine, while the elimination of warfarin and acenocoumarol is almost completely by metabolism. Consequently, the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are also least pronounced in the case of phenprocoumon; this drug seems preferable for therapeutic anticoagulation in poor metabolisers of CYP2C9. In addition to these vitamin K antagonists, oral thrombin inhibitors are currently under clinical development for the prevention and treatment of thromboembolism. Of these, ximelagatran has recently gained marketing authorisation in Europe. These novel drugs all feature some major advantages over traditional anticoagulants, including a wide therapeutic interval, the lack of anticoagulant effect monitoring and a low drug-drug interaction potential. However, they are also characterised by some pitfalls. Amendments of traditional anticoagulant therapy, including self-monitoring of international normalised ratio values or prospective genotyping for individual dose-tailoring may contribute to the continuous use of warfarin, phenprocoumon and acenocoumarol in the future.

Effect of CYP2C9 polymorphisms on pharmacokinetics of nateglinide

Effect of CYP2C9 polymorphisms on pharmacokinetics of nateglinide

Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers

CYP2C9 catalyses the biotransformation of the oral anticoagulants S-warfarin and R- and S-acenocoumarol. According to data obtained in vitro, phenprocoumon is also metabolized by CYP2C9 but the impact of the CYP2C9 polymorphism on phenprocoumon pharmacokinetics has not been studied. Twenty-six healthy heterozygous and homozygous carriers of the CYP2C9 alleles *1 (wild-type), *2 (Arg144Cys), and *3 (Ile359Leu) received a single oral dose of 12 mg of racemic phenprocoumon. Plasma and 12 h urine concentrations of both enantiomers and their monohydroxylated metabolites were measured by high-performance liquid chromatography with mass spectrometry detection. No significant effect of the CYP2C9 variants *2 and *3 on R-phenprocoumon pharmacokinetic parameters was detected, but S-phenprocoumon clearance tended to decrease with increasing number of CYP2C9*2 and *3 alleles. The ratios of S- to R-phenprocoumon plasma clearances were higher with a median of 0.95 in carriers of *1/*1 versus 0.65 in *3/*3 (P < 0.001 for trend). Plasma and urine concentrations of 4'-, 6- and 7-hydroxyphenprocoumon were significantly lower in homozygous carriers of the CYP2C9*2 and *3 variants compared to CYP2C9*1/*1. Carriers of CYP2C9*3/*3 had a median AUC of (R,S) 7-OH-phenprocoumon of only approximately 25% compared to the wild-type genotype. The AUC of (R,S) 6-OH-phenprocoumon was only approximately 50% in CYP2C9*3/*3 compared to the homozygous wild-type genotype. In conclusion, carriers of CYP2C9*2 and *3 alleles had a lower metabolic capacity regarding phenprocoumon hydroxylation than those with CYP2C9*1/*1. However, regarding phenprocoumon hydroxylation CYP2C9 genotypes had only marginal effects on S- and R-phenprocoumon total clearance in healthy volunteers.

Influence of CYP2C9 and CYP2D6 Polymorphisms on the Pharmacokinetics of Nateglinide in Genotyped Healthy Volunteers

The oral hypoglycaemic drug nateglinide is eliminated from the human body via hepatic biotransformation and renal tubular secretion. According to in vitro data, about 70% of nateglinide intrinsic clearance may be mediated by cytochrome P450 (CYP) 2C9 and a smaller fraction by CYP3A4 and CYP2D6. To assess the impact of CYP2C9 polymorphisms and of the CYP2D6 poor metaboliser genotype on the pharmacokinetics of nateglinide and its effects on insulin, glucose and glucagon in plasma. A prospective clinical study in 26 healthy volunteers chosen for their CYP2C9 and CYP2D6 genotype was conducted with individuals carrying wild-type genotype as reference group. Serial plasma nateglinide, glucose, insulin and glucagon concentrations were measured over 34 hours after a 180 mg dose of nateglinide under challenge with 75 g of oral glucose at 0, 4 and 8 hours after nateglinide intake. Kinetics were evaluated by nonparametric methods and by population pharmacokinetic-pharmacodynamic modelling. Significantly reduced oral nateglinide clearance was found in carriers of CYP2C9*3 alleles, (p < 0.01), whereas carriers of CYP2C9*2 alleles had kinetic parameters similar to those of carriers of the wild-type allele (p = nonsignificant). Median total clearances were 7.9, 8.4, 6.5, 6.9, 5.8 and 4.1 L/h in carriers of the CYP2C9 genotypes *1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3. Median clearance in three carriers of two deficient CYP2D6 alleles was 9.4 L/h. These differences in nateglinide kinetics due to CYP2C9 genotypes did not result in statistically significant differences in plasma glucose, insulin and glucagon. Pharmacokinetic-pharmacodynamic modelling revealed a minor effect of CYP2C9 genotype on insulin and glucose, and extrapolations indicated that carriers of the CYP2C9*3/*3 genotype may be at a slightly higher risk of hypoglycaemia compared with carriers of CYP2C9*1, particularly when taking nateglinide doses above 120 mg. The effect of CYP2C9 polymorphisms on nateglinide kinetics may cause a slightly increased risk for hypoglycaemia, which may become relevant in diabetic patients.

Lack of differences in diclofenac (a substrate for CYP2C9) pharmacokinetics in healthy volunteers with respect to the single CYP2C9*3 allele.

Evidence exists to suggest that diclofenac is metabolised by CYP2C9. The present study was undertaken in order to evaluate the effect of the single CYP2C9*3 variant on drug metabolism using diclofenac as a probe drug. A single dose of diclofenac was administered orally to 12 healthy subjects in whom the genotype of CYP2C9 had been determined previously. The disposition kinetics of diclofenac were compared between homozygotes for the wild type (CYP2C9*1/*1, n = 6) and heterozygotes for the Leu359 variant (CYP2C9*1/*3, n = 6). For diclofenac, the following kinetic parameters were observed in the CYP2C9*1/*1 and CYP2C9*1/*3 subjects, respectively (mean +/- SD): apparent oral clearance (ml/kg/h) 355.8 +/- 56.9 and 484.4 +/- 155.3; area under plasma concentration time curve (microg h/ml) 2.7 +/- 0.7 and 1.9 +/- 0.6. The formation clearance of 4'-hydroxydiclofenac (ml/kg/h) was 63.6 +/- 19.1 in the CYP2C9*1/*1 subjects compared with 75.9 +/- 27.6 in the CYP2C9*1/*3 subjects. There were no significant differences in any of the kinetic parameters for either diclofenac disposition or formation clearance of 4'-hydroxydiclofenac between the two genotype groups. Since the disposition kinetics of diclofenac does not change in subjects with the single CYP2C9*3 mutant allele, it is suggested that the effects of CYP2C9 polymorphisms on the drug metabolism tend to be substrate specific.