A low dose of 125 mg tolbutamide can safely and accurately be used for CYP2C9 phenotyping. As a simple metric for CYP2C9 activity, we propose to determine tolbutamide in plasma 24 h after drug intake.

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug-drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

CYP2C9 is the major human enzyme of the cytochrome P450 2C subfamily and metabolizes approximately 10% of all therapeutically relevant drugs. Two inherited SNPs termed CYP2C9*2 (Arg144Cys) and *3 (Ile359Leu) are known to affect catalytic function. Numerous rare or functionally silent polymorphisms have been identified. About 35% of the Caucasian population carries at least one *2 or *3 allele. CYP2C9 metabolizes several oral hypoglycemics, oral anticoagulants, non-steroidal anti-inflammatory drugs and other drugs, including phenytoin, losartan, fluvastatin, and torsemide. In vitro studies with several drugs indicate that the Cys144 (.2) and Leu359 (.3) variants confer only about 70 and 10% of the intrinsic clearance of the wild-type protein (.1), respectively. The clinical pharmacokinetic implications of these polymorphisms vary depending on the enzymes contribution to total oral clearance. Several studies demonstrated that the CYP2C9 polymorphisms are medically important for non-steroidal anti-inflammatory drugs, for oral hypoglycemics, vitamin K antagonistic oral anticoagulants, and phenytoin. In particular, CYP2C9 polymorphisms should be routinely considered in therapy with oral anticoagulants where severe adverse events at initiation of therapy might be reduced by genotyping. CYP2C9 polymorphisms were also clinically associated with side effects of phenytoin, with gastric bleeding during therapy with non-steroidals and with hypoglycemia under oral hypoglycemic drugs. Data appear mature enough for the routine consideration of CYP2C9 genotypes in therapy with acenocoumarol, phenytoin, warfarin, and some other drugs. Nevertheless, it is advisable before the routine clinical use of these genotype data to rigorously test the benefits of genotype-based therapeutic recommendations by randomized controlled clinical trials.

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