These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes.
Midazolam clearance is used to phenotype hepatic CYP3A activity but requires multiple plasma samples following a single intravenous dose. The authors evaluated the use of a limited sampling scheme, using different assay techniques to determine the reproducibility of such a strategy in estimating midazolam AUC. Seventy-three healthy adults received midazolam as a single intravenous bolus dose. At least eight plasma samples were collected from each subject and were assayed using either LC/MS/MS or electron capture gas chromatography. Eleven subjects were randomly selected for the training set using stepwise linear regression to determine relationships between midazolam plasma concentrations and AUC. Validation of the predictive equations was done using the remaining 62 subjects. Mean percent error (MPE), mean absolute error (MAE), and root mean square error (RMSE) were calculated to determine bias and precision. Based on the training set, five models were generated with coefficients of determination ranging from 0.87 to 0.95. Validation showed that MPE, MAE, and RMSE values were acceptable for three of the models. Intrasubject reproducibility was good. In addition, training set datafrom one institution were able to predict data from the other two institutions using other assay techniques. Minimized plasma sampling mayprovide a simpler method for estimating midazolam AUC for CYP3A phenotyping. A limited sampling strategy is more convenient and cost-effective than standard sampling strategies and is applicable to more than one assay technique.
Evidence for the selectivity of S-warfarin metabolism by CYP2C9 is substantial, suggesting that warfarin may be a potential CYP2C9 phenotyping probe. It is, however, limited by its ability to elevate the international normalized ratio (INR) and potentially cause bleeding. The effect of vitamin K to attenuate the elevation of INR may enable the safe use of warfarin as a probe. The objective of this study was to investigate the pharmacokinetics and pharmacodynamics of S- and R-warfarin in plasma following the administration of warfarin alone versus warfarin and vitamin K in CYP2C9*1 homozygotes. Healthy adults received, in a randomized crossover fashion in a fasted state, warfarin 10 mg orally or warfarin 10 mg plus vitamin K 10 mg orally. Blood samples were obtained over 5 days during each phase. INR measurements were obtained at baseline and day 2 in each phase. INR, AUC0-infinity, and t1/2 of plasma S- and R-warfarin were examined. Eleven CYP2C9*1 homozygotes (3 men, 8 women) were enrolled. INR at day 2 following warfarin 10 mg was 1.18 +/- 0.19, which differed significantly from baseline (INR = 1.00 +/- 0.05) and warfarin with vitamin K (INR = 1.06 +/- 0.07). INR at baseline was not significantly different from warfarin with vitamin K. t1/2 and AUC0-infinity of both enantiomers did not significantly differ between the phases. It was concluded that INR is apparently attenuated by concomitant administration of a single dose of vitamin K without affecting the pharmacokinetics of either warfarin stereoisomer. Warfarin 10 mg may be safely used as a CYP2C9 probe in *1 homozygotes when given concomitantly with 10 mg of oral vitamin K.
S-warfarin area under the concentration-time curve (AUC(0- infinity )) and clearance are used as measures of cytochrome p450 (CYP) 2C9 activity. In addition, warfarin S/R ratios are used to assess CYP2C9 activity. The determination of S-warfarin AUC(0- infinity ) requires multiple blood samples. Limited sampling strategy (LSS) is a validated technique that estimates AUC(0- infinity ) using limited blood samples. The objective of this study was to evaluate LSS of S-warfarin concentrations and warfarin S/R ratios to predict S-warfarin AUC(0- infinity ) during CYP2C9 baseline activity and inhibition with fluvastatin. Fifty-one healthy subjects, genotyped as CYP2C9 extensive metabolizers, were administered oral warfarin 10 mg. Blood samples were collected over 96 hours. S-warfarin AUC(0- infinity ) equations were derived from a training set of 20 subjects using multiple linear regression. Validation of the equations used data from the remaining 31 subjects. All derived equations were within acceptable limits for measures of bias and precision. Single-point and two-point S-warfarin concentrations, but not warfarin S/R ratios, were predictive of S-warfarin AUC(0- infinity ) during CYP2C9 baseline activity and inhibition. No correlation was observed between CYP2C9(*)1/(*)1 and (*)1/(*)2 genotypes and either S-warfarin concentrations or warfarin S/R ratios. The equation using two-point S-warfarin concentrations at 24 and 48 hours was the most accurate predictor of S-warfarin AUC(0- infinity ). LSS using S-warfarin concentrations is an efficient and accurate technique to evaluate S-warfarin AUC(0- infinity ) when using warfarin as a CYP2C9 probe drug.
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