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-').

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

Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady-state. Using areas under the plasma concentration-time curves for each of the dimethylxanthines derived from CA in the steady-state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (± s.d.) fractional conversion of CA to PX, TB and TP was 79.6 + 21.0%, 10.8 + 2.4% and 3.7 + 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 + 5.4%, 12.1 + 4.1% and 4.0 + 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8-fold and 23-fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed.

Paracetamol disposition was studied in groups of pregnant and non-pregnant women of comparable age. Paracetamol apparent oral clearance was 58% higher and elimination half-life was 28% lower in the pregnant women compared to the control group. The higher clearance in the pregnant women was due to increased activity of the glucuronidation (75% higher) and oxidative (88% higher) pathways of paracetamol metabolism. There was no difference between the two groups in paracetamol sulphation or renal clearance of unchanged drug.

Paracetamol metabolism was compared in groups of young adult (mean age 20.8 years) and elderly (mean 79.3 years) males. Apparent oral clearance and half-life and partial metabolic clearances to the glucuronide and glutathione-derived conjugates of paracetamol were not significantly different between the two groups. However, the partial metabolic clearance to paracetamol sulphate was 23.1% lower and renal clearance of unchanged drug was 42.9% lower in the elderly compared to the young adults. Despite the decreased clearance by these pathways, reduction in paracetamol dosage should not be necessary in the elderly.