Pharmacokinetic and pharmacodynamic assessment of a five‐probe metabolic cocktail for CYPs 1A2, 3A4, 2C9, 2D6 and 2E1

Abstract

AimsThe primary objectives of the present study were to establish whether there was a pharmacokinetic or pharmacodynamic interaction between the probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), debrisoquine (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4), when administered in combination as a cocktail. Furthermore, the tolerability of these probe drugs, both alone and in combination as a cocktail was assessed. MethodsTwelve healthy volunteer subjects (age range 22-48 years) were entered into an open, fixed sequence, 6-limb, single centre study. The randomization was such that all drugs were given individually followed by the full 'cocktail' as the last treatment limb. The phenotypic index used to assess the intrinsic activity of the CYP isoforms included metabolite/parent ratios in plasma and urine (CYPs 1A2, 2E1 & 2C9), parent/metabolite ratios in urine (CYP2D6) and plasma AUC last (CYP3A4). Blood pressure and blood glucose measurements were used to assess pharmacodynamic interactions. Tolerability was assessed through reporting of adverse events. ResultsOverall, there was little evidence that the probe drugs interacted metabolically when co-administered as the cocktail. The ratio of the geometric mean (and 90% confidence interval) of the phenotypic index, obtained after administration of the probe as part of the cocktail and when given alone were: caffeine, 0.86 (0.67-1.10), midazolam, 0.96 (0.74-1.24), tolbutamide, 0.86 (0.72-1.03), debrisoquine 1.04 (0.97-1.12) and chlorzoxazone, 0.95 (0.86-1.05). There was no difference in blood pressure and blood glucose concentrations following the cocktail and dosing of the individual probes. There was no effect on ECG recordings at any time-point. The adverse events reported for individual drug administrations were mild, transient and expected. Overall no more adverse events were reported on the cocktail study days than on the days when the drugs were administered alone. ConclusionsThe five probe drugs when coadministered, in this dosing regimen, demonstrated no evidence of either a metabolic or pharmacodynamic interaction that might confound the conclusions drawn during a cocktail study. The present cocktail methodology has the potential to become a useful tool to aid the detection of clinically impor tant drugdrug interactions during drug development. Assessment of the interactions of five co-administered probe drugsBr J Clin Pharmacol 57:2 163

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

“…In contrast to other existing cocktails (e.g., Frye et al, 1997;Palmer et al, 2001;Blakey et al, 2004), the cocktail used here has several useful peculiarities, including semisequential midazolam administration, allowing the assessment of hepatic and intestinal CYP3A4 activity within 1 day; low doses for all substances, minimizing the risk for adverse reactions; the inclusion of optional cocktail components; and the use of fully validated metrics for all P450s included.…”

“…Here, the low-dose cocktail strategy could be shown to be an effective tool to assess the drug-drug interactions profile of propiverine in vivo. All probe substrates used in this cocktail approach have been previously shown to be enzyme-selective substrates without relevant mutual interaction in vivo (Endres et al, 1996;Frye et al, 1997;Streetman et al, 2000b;Bruce et al, 2001;Palmer et al, 2001;Wang et al, 2001;Zhu et al, 2001;Blakey et al, 2004). The composition of the cocktail used here was tailored primarily with respect to the previous information obtained in in vitro studies, suggesting that any clinically relevant interaction of propiverine with cytochrome P450 enzymes as a substrate, inhibitor, and/or inducer would mainly concern CYP3A4 and possibly also CYP2C9 and/or CYP2C19.…”

“…Whereas in vitro studies using human liver microsomes or expressed enzymes provide only preliminary information about P450s that are likely to be affected clinically, in vivo phenotyping provides more conclusive information on how the test drug might interfere with the respective P450s in patients (Blakey et al, 2004). Phenotyping, i.e., estimation of enzyme activity by administration of a selective substrate for this enzyme and subsequent determination of pharmacokinetic parameters reflecting its activity, is considered to be the most favorable method for assessment of actual metabolic capacities resulting from both intrinsic and extrinsic factors (Streetman et al, 2000a).…”

Closed-loop control of cellular functions using combinatory drugs guided by a stochastic search algorithm

“…A mixture of drugs, in many cases, is more effective than using a single stimulus (1)(2)(3)(4)(5). However, the combination of various possible concentrations of a set of agonists creates a large testing parametric space.…”

Cardiac Arrest and Therapeutic Hypothermia Decrease Isoform-Specific Cytochrome P450 Drug Metabolism

“…A probe cocktail of midazolam, diclofenac, dextromethorphan, and chlorzoxazone was used for the phenotypic assessment of CYP3A, CYP2C, CYP2D, and CYP2E1 activity, respectively. In vivo validation of all these probe drugs or in combination in cocktail has been previously performed (Scott et al, 1999;Blakey et al, 2004;Krösser et al, 2006;Ryu et al, 2007;Ghassabian et al, 2009;Xia et al, 2010). Midazolam, diclofenac, dextromethorphan, and chlorzoxazone were also chosen on the basis of their relative specificity, their relatively short half-life, and their prior clinical use as probe drugs (Streetman et al, 2000;Frye 2004).…”