PHARMACOKINETICS AND DISPOSITION E. J. Seaber á G. Ridout á G. Layton J. Posner á R. W. Peck The novel anti-migraine compound zolmitriptan (Zomig 311C90) has no clinically signi®cant interactions with paracetamol or metoclopramide Received: 9 April 1997 / Accepted in revised form: 24 July 1997 Abstract Objective: This study investigated potential pharmacokinetic or pharmacodynamic interactions be- tween the novel anti-migraine compound zolmitriptan (Zomig, formerly 311C90) and paracetamol and/or metoclopramide. Methods: In an open-label, randomised, crossover study, 15 healthy volunteers received single oral doses of 10 mg zolmitriptan alone, 1g paracetamol alone, 10 mg zolmitriptan + 1 g paracetamol, 10 mg zolmitriptan + 10 mg metoclopramide or 10 mg zolmitriptan + 1 g paracetamol + 10 mg metoclopramide on ®ve separate occasions. Results: Metoclopramide had no signi®cant eects on the pharmacokinetics of zolmitriptan or the active zolmitriptan metabolite 183C91, nor did it aect inter- actions between zolmitriptan and paracetamol. Para- cetamol marginally increased the maximum plasma concentration (C max ) (11%) and the area under the curve (AUC) (11%) and reduced the renal clearance of zolmitriptan (9%); similar small eects were seen on 183C91. The AUC, C max and half-life of paracetamol were reduced by concomitant zolmitriptan (by 11%, 31% and 8%, respectively), whilst the mean residence time showed a small increase (+0.7 h). There was a trend towards a transient increase in blood pressure following all regimens containing zolmitriptan; this ef- fect was small, was consistent between all zolmitriptan regimens as well as with previous studies, and was considered to be clinically insigni®cant. Zolmitriptan was well tolerated after all treatment regimens. Conclusion: Concomitant administration of zolmitriptan and paracetamol resulted in a slight increase in bio- availability of zolmitriptan and a reduced rate and ex- tent of paracetamol absorption. These ®ndings are considered to be of no clinical signi®cance and there is no reason to avoid concomitant administration of pa- racetamol and/or metoclopramide with zolmitriptan. Key words Zolmitriptan, Migraine Introduction Migraine is a relatively common incapacitating condi- tion [1] for which both acute and prophylactic therapy remains unsatisfactory for many patients. Conventional acute treatments include analgesics (e.g. aspirin or par- acetamol) which are frequently taken in conjunction with anti-emetics (e.g. metoclopramide). In addition to treating nausea, anti-emetics may also enhance analgesic drug absorption which may be impaired by gastric stasis during a migraine attack. Patients whose migraine does not respond to these analgesics are often treated with ergot alkaloids, although the value of these agents is limited by poor oral absorption and circulatory adverse eects [2, 3]. Zolmitriptan (Zomig, formerly 311C90) is a potent and selective agonist at 5-HT 1B/1D receptors, with both central and peripheral actions. Animal models have shown that zolmitriptan is up to three times more potent than another 5-HT 1 receptor agonist, sumatriptan, in terms of neuronal inhibition and vasoconstriction [4, 5]. Moreover, experimental animal data have shown that zolmitriptan is able to access important central sites in- volved in cranial nociceptive input [6]. Zolmitriptan has proved highly eective in initial clinical trials in patients with acute migraine. In a double-blind, placebo-con- trolled study, zolmitriptan 5 mg resulted in a signi®cant improvement in headache in 66% of patients at 2 h, with 39% of patients pain-free at this time [7]. Similar ecacy is reported at doses of 2.5 mg with 65% of patients re- porting a headache improvement at 2 h [8]. Edmeads reported that over 90% of migraine suf- ferers had taken over-the-counter analgesics [9]. There- fore, it is possible that metoclopramide and paracetamol Eur J Clin Pharmacol (1997) 53: 229±234 Ó Springer-Verlag 1997 E.J. Seaber (&) á G. Ridout á G. Layton á J. Posner á R.W. Peck Glaxo Wellcome Research and Development, Greenford Road, Greenford, Middlesex UB6 OHE, UK Tel. +44 181 966 4410; Fax +44 181 966 2898