Xia Li*, Max Taubert, Yingying Tian, Malaz Gazzaz, Uwe Fuhr*
Department of Pharmacology, Clinical Pharmacology, Cologne University Hospital, Cologne, Germany
Objectives: We conducted a cocktail drug-drug interaction study to evaluate the effect of acute ethanol consumption on the most important drug-metabolising cytochrome P450 enzymes, NAT2 and P-glycoprotein. The aim of the present evaluation was to accurately describe internal ethanol exposure in this study. Primary metabolism of ethanol occurs essentially in the liver and is mainly mediated by a group of alcohol dehydrogenase isoforms, but to a minor extent also by other enzymes including cytochrome P450 CYP2E1. The availability of NAD+ limits ethanol oxidation, causing saturating kinetics.
Methods: Data were obtained from an open-labeled, single-center, two-way, cross-over study in 16 healthy volunteers (8 males, 8 females), aged from 20 to 52 years old, with a body weight (BW) from 54.5 to 97.0 kg. During test period, the initial ethanol doses (ml) were 1.925 × BW and 1.65 × BW for male and female,respectively. After 2 hours, the cocktail consisting of omeprazole, tolbutamide, caffeine, dextromethorphan and digoxin was given. Thereafter, additional doses of ethanol were given five times at 4 hours intervals: males, 0.77 × body weight (kg); female, 0.66 × body weight (kg). During the reference period, the cocktail was administered without ethanol. Blood ethanol concentrations C (measured at 9 time points by gas chromatography) and breath concentrations CB (measured at 6 time points, Draeger breath analyzer Alcotest 7410 plus, Drägerwerk AG, Lübeck, Germany) were collected. CB was assumed to be related to C as described by equation 1: C= M × CB. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modeling (NONMEM 7.2.0).
Results: A one-compartment model with a single Michaelis-Menten elimination pathway was not only suitable as the basic model,but also was clearly better than linear or exponential concentration decline (ΔOFV, -9.291). The value of Km could not be estimated and thus was fixed as 0.0821 g/L according to the literature [1]. As for covariates, volume of distribution V had a significant relationship with subject body weight (ΔOFV, -152.53), and sex had a small albeit significant effect on maximal elimination capacity VM (ΔOFV, -19.285). Covariate model:
Vmax = θ[VM] *(1+ (SEX-1)* θ[Sex on Vmax ] (0 = Male; 1 = Female); V= θ[V] * (Weight/71.6) ^ θ [Weight on V]
The mean and relative standard error of the parameter estimates derived from the study were Vmax 7.01 g/h (3 %), V 31.7 L(3 %), Ka 1.4 h-1 (7 %), M 1850 (2 %), θ [Weight on V] 1.44 (9 %), θ [Sex on Vmax -0.39 (18 %). Although the data were obtained from blood and from breath ethanol concentration, they were integrated well with the introduction of equation 1.
Conclusions: Despite the involvement of multiple enzymes, a simple model was suitable to describe internal ethanol exposure. Results are in accordance with published data.
References:
[1] Wilkinson PK, Sedman AJ, Sakmar E, Earhart RH, Weldler DJ, Wagner JG. Blood ethanol concentrations during and following constantrate intravenous infusion of alcohol. Clin Pharmacol Therap 19, 1975. 213-223.
Reference: PAGE 25 (2016) Abstr 5864 [www.page-meeting.org/?abstract=5864]
Poster: Methodology - Other topics