SHORT COMMUNICATION R.G. Dattani Æ F. Harry Æ A.D. Hutchings P.A. Routledge The effects of acute ethanol intake on isoniazid pharmacokinetics Received: 12 December 2003 / Accepted: 16 August 2004 / Published online: 2 October 2004 Ó Springer-Verlag 2004 Abstract Aim: To assess effects of acute ethanol intake on the pharmacokinetics of isoniazid in healthy male vol- unteers. Methods: Sixteen healthy male, drug-free subjects were studied. Each received in the fasting state, on two occa- sions separated by at least 1 week, isoniazid (200 mg or- ally). On one occasion (assigned randomly), subjects received ethanol 0.73 g/kg, 1 h before isoniazid, followed by 0.11 g/kg ethanol orally every hour thereafter for 7 h. Plasma isoniazid and acetylisoniazid concentrations were measured by means of high-performance liquid chroma- tography. Blood ethanol concentrations were measured hourly by breath analysis. Plasma concentrations of iso- niazid and acetylisoniazid were analysed using TOPFIT software. Results: Peak concentrations of isoniazid were reached within 90 min, in both the ethanol-treated and control groups. The ethanol dosage regimen used resulted in peak blood ethanol concentrations between 78 mg/l and 103 mg/l. There was no significant difference in area under the curve, half-life of elimination or the ratio of acetyli- soniazid to isoniazid (AcINH/INH) in the sample withdrawn 3 h after isoniazid dose. Acetylator pheno- type for patients was the same in both phases, whether assessed by half-life of isoniazid or the AcINH/INH ratio at 3 h. Conclusions: Acute ethanol intake at this dose is unlikely to affect results of acetylation studies in which isoniazid is used as a substrate, whether the half-life of isoniazid or the AcINH /INH ratio at 3 h is used to phenotype patients. Keywords Isoniazid Æ Ethanol Æ Acetylator status Æ Acetylation Æ Pharmacokinetics Æ Drug interaction Introduction The rate at which an individual acetylates a drug is bimodally distributed, with subjects being classified as either slow or fast acetylators. From a clinical point of view, this polymorphism is of great importance with respect to adverse reactions and therapeutic effects. In general, at any given dose, the occurrence of ad- verse reactions to polymorphically acetylated drugs is greater in slow acetylators whilst therapeutic effects may be sub-optimal in rapid acetylators when they are taking dosages appropriate for slow acetylators [1]. For this reason, acetylation phenotyping has often been used as a predictor of toxicity or of dose requirement [2]. Many complex factors are known to interfere with the ability to measure reliably the acetylating capacity of an individual. For example, sulphamethazine and pro- cainamide clearance by non-renal routes is enhanced by acute administration of ethanol in man [3–5]. In some slow acetylators, the extent of acetylation measured in blood increased so much that they would have been misclassified as rapid acetylators, according to conven- tional criteria [5]. Since both these drugs are acetylated, we investigated the effects of acute ethanol administra- tion in volunteers receiving isoniazid (INH), which is also acetylated in man. This compound is of particular interest in that it is widely used to examine acetylator status [6] and has several advantages over other sub- strates used for this purpose [7–9]. Furthermore, a single sample (plasma or saliva) INH test has proven to be as reliable as the conventional tests whilst being less inva- sive [10–12]. R.G. Dattani Æ F. Harry Æ A.D. Hutchings Æ P.A. Routledge Department of Pharmacology, Therapeutics and Toxicology, UWCM Academic Centre, Llandough Hospital, University of Wales College of Medicine, Cardiff, CF64 2XX, UK Present address: R.G. Dattani (&) Union Academic Centre, Llandough Hospital, Cardiff, CF64 2XX, UK E-mail: rupendattani@hotmail.com Tel.: +44-1222171814 Eur J Clin Pharmacol (2004) 60: 679–682 DOI 10.1007/s00228-004-0828-y