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The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate).In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period.Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P = 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02).CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.

1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype.A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 CT genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h.Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC(PT) (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC(PT) (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC(PT((R)-warfarin)) : AUC(PT((S)-warfarin))) was 1.21 fold higher (95% CI 1.05, 1.41, P0.02) in subjects of VKORC1 TT genotype compared with the CC genotype.(R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Razlika u reakciji na lijek je vrlo česta kod pacijenata. U novije vrijeme, farmakogenetika se bavi mnoštvom reakcija na lijekove među pacijentima. Različita reakcija na lijek je uvjetovana raznim razlozima kao što su genetička konstitucija, okolišni čimbenici i doziranje lijeka. Otkrića farmakogenetike su društveno, medicinski, znanstveno i gospodarski bitni. U budućnosti će genetičko profiliranje populacije omogućiti zdravstvenoj skrbi predviđanje reakcije na lijekove i razvoj DNA testova. Ne možemo se uvijek osloniti na farmakogenetiku u reakciji na lijekove jer postoje i negenetički faktori koji mogu utjecati na reakciju i tako prouzročiti poteškoće pri dijagnozi i odabiru lijeka. Ipak, ušli smo u novu eru farmakogenetike, koja se čini jako obećavajućom u potpori donošenja terapeutske odluke, predviđanju pacijenata koji će najvjerojatnije dobro reagirati na određeni lijek ili kod kojih će lijek polučiti optimalne rezultate. The difference in drug response is very common among patients. Recently, phamacogenetics is dealing with variety of responses to medications for patients. The different response to drugs due to various reasons such as genetics constitutions, environmental factors and drug dosages. Findings from pharmacogenetics are socially, medically, scientifically and economically important. Genetic profiling of the population in the future will allow medical care predicting drug response or the development of DNA tests. We can not always rely on pharmacogentics base drug response because there are also non-genetic factors that can affect the response to drug, thus causing difficulty in diagnosis and choice of drug. Now, we have entered a new era with pharmacogenetics, which appear highly promising in enhancing the support to therapeutic decision- making, predicting patients who are most likely to respond best to a particular drug, or in whom the drug will yield optimal effects.