Combined phenotypic assessment of cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A, N-acetyltransferase-2, and xanthine oxidase activities with the “Cooperstown 5+1 cocktail”

Abstract

Previously, we have validated a 4-drug phenotyping cocktail, the "Cooperstown cocktail," using caffeine (cytochrome p450 [CYP] 1A2, N-acetyltransferase-2 [NAT2], and xanthine oxidase [XO]), dextromethorphan (CYP2D6), omeprazole (CYP2C19), and intravenous midazolam (hepatic CYP3A). Data suggest that warfarin can be used as a safe and accurate biomarker for CYP2C9, and if warfarin is administered with vitamin K, the pharmacodynamic effect is ablated. Twelve subjects received the Cooperstown cocktail, warfarin plus vitamin K, and both sets of biomarkers (Cooperstown 5+1 cocktail) in a randomized crossover fashion. On the basis of log-transformed data and a paired t test, no significant difference was seen for S-warfarin area under the serum concentration-time curve from time 0 to infinity (P =.09), omeprazole metabolic ratio (P =.374), caffeine metabolic ratio (P =.169 for CYP1A2 activity), midazolam plasma clearance (P =.573), or dextromethorphan metabolic ratio (P =.747) with the Cooperstown cocktail, warfarin plus vitamin K alone, or the Cooperstown 5+1 cocktail. During drug administration, the only side effect was mild and short-lived sedation after intravenous midazolam administration. Phenotypic measurements were in concordance with the subject's CYP2C9, CYP2C19, and CYP2D6 genotypes. The Cooperstown 5+1 cocktail may be used to simultaneously assess the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A, NAT2, and XO.

Simultaneous LC-MS/MS Analysis of the Plasma Concentrations of a Cocktail of 5 Cytochrome P450 Substrate Drugs and Their Metabolites

“…Previously reported cocktail testing methods that assayed for CYP probe drugs required a dual analytical approach subsequent to multiple sample preparations. [6][7][8][9] In contrast, we used the Ostro 96-well plate procedure in this study. This method is based on high affinity for phospholipids, with low selectivity toward a wide range of basic, neutral, and acidic compounds.…”

“…Since the Pittsburgh cocktail was first introduced in 1997, 6) several cocktails, including the Cooperstown 5+ 1 cocktail, 7) the Karolinska cocktail, and the Inje cocktail, have been developed. 8,9) However, these approaches are somewhat limited because some probes used in these cocktails, such as mephenytoin and debrisoquine, are no longer available for clinical use in many parts of the world.…”

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

“…A common strategy is to rank order the likelihood of in vivo DDI and conduct a probe substrate interaction in the clinic targeting the most potent interaction, based on the in vitro DDI data (Obach et al, 2005). Alternatively, a clinical study, using a cocktail of probe substrates, has been used to assess DDI potential (Streetman et al, 2000;Chainuvati et al, 2003). Both approaches have their merits (Bjornsson et al, 2003;U.S.…”

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

“…Many cocktail studies have been conducted using humans, such as the Cooperstown 5+1 cocktail [31], Karolinska cocktail [32], Inje cocktail [33], and Basal cocktail [34]. Of these cocktail methods, the Inje cocktail includes all commercially available drugs such as caffeine (human CYP1A2 substrate), losartan (human CYP2C9 substrate), omeprazole (human CYP2C19 substrate), dextromethorphan (human CYP2D6 substrate), and midazolam (human CYP3A substrate) for which the human pharmacokinetic properties are known [33].…”