The novel anti-migraine compound zolmitriptan (Zomig 311C90) has no clinically significant interactions with paracetamol or metoclopramide.

OBJECTIVE: This study investigated potential pharmacokinetic or pharmacodynamic interactions between 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, 1 g 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 five separate occasions. RESULTS: Metoclopramide had no significant effects on the pharmacokinetics of zolmitriptan or the active zolmitriptan metabolite 183C91, nor did it affect interactions between zolmitriptan and paracetamol. Paracetamol marginally increased the maximum plasma concentration (Cmax) (11%) and the area under the curve (AUC) (11%) and reduced the renal clearance of zolmitriptan (9%); similar small effects were seen on 183C91. The AUC, Cmax 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 effect was small, was consistent between all zolmitriptan regimens as well as with previous studies, and was considered to be clinically insignificant. Zolmitriptan was well tolerated after all treatment regimens. CONCLUSION: Concomitant administration of zolmitriptan and paracetamol resulted in a slight increase in bioavailability of zolmitriptan and a reduced rate and extent of paracetamol absorption. These findings are considered to be of no clinical significance and there is no reason to avoid concomitant administration of paracetamol and/or metoclopramide with zolmitriptan.

Determination of the potent antiprotozoal compound atovaquone in plasma using liquid-liquid extraction followed by reversed-phase high-performance liquid chromatography with ultraviolet detection.

A specific and robust method is presented for the determination of atovaquone in plasma. Atovaquone is a potent antiprotozoal compound for use in immunocompromised patients who are intolerant of conventional therapies. The method involves a liquid-liquid extraction of the compound into hexane modified with 2% (v/v) isoamyl alcohol. The processed extracts are analysed by reversed-phase high-performance liquid chromatography with ultraviolet detection at 254 nm. The assay has a limit of quantification of 0.1 microgram/ml and is linear between 0.1 and 50 micrograms/ml. The method has been applied to many clinical studies and has been demonstrated to be precise and accurate with high sample throughput. Atovaquone is not significantly metabolised in humans.

Examination of some factors responsible for a food-induced increase in absorption of atovaquone.

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and Cmax 5.3-fold (4.3-6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and Cmax 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and Cmax 5.6-fold (3.8-8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and Cmax 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8-fold (1.2-2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and Cmax by 1.5-fold (0.98-2.4).(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of structure-penetration relationships in percutaneous absorption.

Prediction of chemical transport across skin is important both to the optimization of topical and transdermal drug delivery and to the assessment of risk following dermal exposure. To facilitate estimation of percutaneous absorption, a number of model in vitro experimental systems have been developed. However, the predictive applicability of the different approaches (with respect to human skin penetration), and the quantitative aspects of the structure-permeation behavior revealed, have not been critically evaluated. The objectives of this paper are to collect, from the literature, the more systematic investigations pertaining to chemical transport across the skin, to quantify the dependence of permeation on the lipophilicity of the penetrants studied, and to assess the relative utility of model systems for the prediction of percutaneous absorption. The categories of chemicals addressed in the survey include n-alkanols, para-substituted phenols, steroids and non-steroidal anti-inflammatory drugs. The experimental systems, used in the studies considered, involve, primarily, steady-state transport measurements across excised skin taken from either human cadavers or hairless mice. Favorable comparisons of these data to solute flux across simple organic liquid membranes are possible. Overall, general patterns of behavior emerge from the analysis such that qualitative predictions can be made. From a quantitative standpoint, though, it is clear that additional "structure-activity" work is necessary to provide appropriate equations that can relate penetration between different test systems and between different chemical classes.

The effects of zwitterionic surfactants on skin barrier function.

The action of five zwitterionic surfactants on the barrier function of hairless mouse skin has been studied in vitro. The surfactants considered were dodecylbetaine and hexadecylbetaine (C12BET and C16BET, respectively), hexadecylsulfobetaine (C16SUB), N,N-dimethyl-N-dodecylamine oxide (C12AO), and dodecyltrimethylammonium bromide (C12TAB). Excised skin was pretreated with each surfactant, at various concentrations, for 16 hr, following which the permeation of a model compound, nicotinamide, was measured. The action of the surfactants was assessed by comparing nicotinamide flux through surfactant-pretreated skin with that across control membranes which were exposed to buffer alone for 16 hr. All surfactants decreased skin barrier function to some extent. The degree of nicotinamide penetration enhancement induced was correlated with the ratio of the surfactant pretreatment concentration to the surfactant critical micelle concentration, suggesting that solubilization of stratum corneum lipids may be an important mechanism in explaining the effects observed. More detailed studies with 14C-radiolabeled C12BET and C16BET showed that the dodecyl analog was itself well absorbed, whereas the C16 compound partitioned into the skin favorably but then transferred only very slowly into the receptor phase. These observations were consistent with toxicity studies (albeit at much higher concentrations in a different animal model, the rat) which indicated that the dermal LD50 of C12BET was significantly less than that of C16BET (the value for which was so large that it could not be reliably determined). Overall, this study provides, we believe, useful information pertinent to the potential dermal toxicity of the surfactants considered following occupational or environmental exposure.

Enhanced in vitro skin permeation of cationic drugs.

The lipophilicity of cationic drugs can be increased by forming ion pairs with the carboxylate anion of fatty acids. Transport of cations across an isopropyl myristate (IPM) membrane was facilitated in the presence of oleic acid and lauric acid, providing an appropriate pH gradient existed. Enhancement of in vitro skin permeation of various drugs, in the presence of fatty acids, was shown to be more dramatic with the slow-permeating neutral caffeine and anionic salicylate. Since both molecules are unable to form ion pairs it is probable that the fatty acids are capable of exerting a disruptive influence on the skin. The cationic drugs appeared to traverse excised human skin more rapidly than predicted by the model membrane data. This may be due to ion pairing with free fatty acids or other anionic groups within the skin. Consequently, the enhancing ability of fatty acids was less marked for neutral or anionic permeants.

Pharmacokinetic considerations in the use of newer transdermal formulations.

This review addresses the pharmacokinetics and pharmacodynamics of transdermally delivered drugs. The systemic input of drugs via the skin has attracted considerable interest over the past 15 years. The early promise of the administration route has, to some extent, been realised with the approval and successful launching of transdermal formulations of hyoscine (scopolamine), glyceryl trinitrate (nitroglycerin), clonidine and oestradiol. The further application of transdermal delivery, however, will require additional effort. While other molecules (e.g. testosterone, fentanyl, nicotine) may ultimately be administered in this way, important questions pertaining to pharmacology (tolerance), toxicity (irritation, sensitisation) and dose sufficiency (penetration enhancement) remain. These problems are illustrated using information which has been published in the literature. Overall, while the enthusiasm for attraction and benefits of transdermal delivery remain evident, it is clear that future successes will demand a heightened level of commitment and skill from the pharmaceutical scientist.