1 The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers after oral administration of each compound on separate occasions. 2 The total plasma clearances of CA and PX were similar in value (2.07 and 2.20 ml minkg-', respectively) as were those for TP and TB (0.93 and 1.20 ml min-' kg-', respectively).The unbound plasma clearances of CA and PX were also similar in magnitude (3.11 and 4.14 ml min-' kg-', respectively) as were those of TP and TB (1.61 and 1.39 ml min-t kg-', respectively). 3 The half-lives of TP and TB (6.2 and 7.2 h, respectively) were significantly longer than those of CA and PX (4.1 and 3.1 h, respectively).4 The volume of distribution at steady state of TP (0.441 kg-') was lower than that of the other methylxanthines (0.63-0.721 kg-1). The unbound volume of distribution of TP (0.77 1 kg-) was however the same as that of TB (0.791 kg-') whereas the unbound volume of distribution of PX (1.18 1 kg-1) was similar to that of CA (1.06 1 kg-').

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1 Paracetamol metabolism was investigated in eight healthy males, eight healthy females and eight healthy females receiving oral contraceptive steroids (OCS). 2 Paracetamol clearance was 22% greater in males compared to the control female group. This difference was entirely due to increased activity of the glucuronidation pathway in males, there being no sex-related differences in the sulphation or oxidative metabolism of paracetamol. 3 Paracetamol clearance in females using OCS was 49% greater than in the control females. Glucuronidation and oxidative metabolism were both induced in OCS users (by 78% and 36% respectively) but sulphation was not altered. 4 Although sex-related differences in paracetamol metabolism are unlikely to be of clinical importance, induction of paracetamol metabolism by OCS may have clinical and toxicological consequences.

1 A radiometric high performance liquid chromatographic method is described for the assay of theophylline metabolism in vitro by the microsomal fraction of human liver. 2 Formation of the three metabolites of theophylline (3-methylxanthine, 1-methylxanthine and 1 ,3-dimethyluric acid) were linear with protein concentrations to 4 mg mland with incubation times up to 180 min. 3 The coefficients of variation for the formation of 3-methylxanthine, 1-methylxanthine and 1,3-dimethyluric acid were 1.2%, 1% and 1.6%, respectively. 4 Theophylline is metabolised by microsomal enzymes with a requirement for NADPH. 5 The mean (n = 7) Km values for 1-demethylation, 3-demethylation and 8-hydroxylation were 545, 630 and 788 FtM, respectively, and the mean Vmax values were 2.65, 2.84 and 11.23 pmol min-' mg-', respectively. 6 There was a high correlation between the Km and Vmax values for the two demethylation pathways suggesting that the demethylations are performed by the same enzyme. 7 Overall the in vitro studies are consistent with the in vivo results which suggest the involvement of two cytochrome P-450 isozymes in the metabolism of theophylline.Keywords theophylline metabolism cytochrome P-450 in vitro