Application of Theophylline Metabolite Assays to the Exploration of Liver Microsome Oxidative Function in Man

Abstract

The effects on theophylline oxidative metabolism of 3 inhibitors of liver microsome activity--cimetidine, troleandomycin and ketoconazole--were investigated in 6 healthy volunteers. The 3 compounds increased plasma theophylline half-life by 73.6 +/- 15.6% (P less than 0.01), 107.8 +/- 9.7% (P less than 0.001) and 21.7 +/- 6.8% (P less than 0.02), respectively, and reduced plasma theophylline clearance by 38.3 +/- 4.8% (P less than 0.001), 51.4 +/- 2.4% (P less than 0.001), and 8.9 +/- 7.8% (NS), respectively. Troleandomycin inhibited to the same extent the 2 theophylline metabolism pathways: N-demethylation resulting in the formation of 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX), and 8-hydroxylation resulting in the formation of 1,3-dimethyluric acid (1,3-DMU). The production clearances of these metabolites were almost equally depressed by 60.2 +/- 3.9%, 60.2 +/- 2.1%, and 51.7 +/- 4.5%, respectively. Cimetidine predominantly inhibited the N-demethylation pathway; the production clearances of 1-MU and 3-MX were depressed by 58.5 +/- 4.0% and 57.5 +/- 4.1% (P less than 0.001), respectively, whereas the production clearance of 1,3-DMU was depressed by 38.3 +/- 6.1% (P less than 0.001). Ketoconazole had no significant effect on the produciton clearances of theophylline metabolites. Measurement of theophylline metabolite formation clearances might be a useful test to explore liver microsome oxidative function.

Metabolism of Ramelteon in Human Liver Microsomes and Correlation with the Effect of Fluvoxamine on Ramelteon Pharmacokinetics

“…Fluvoxamine is known to inhibit this enzyme potently in vitro and in vivo; however, to explain the Ͼ100-fold interaction CYP1A2 would need to be virtually the only enzyme involved in ramelteon clearance. This is clearly not the case because coadministration of ramelteon with ketoconazole and fluconazole both yield DDI (1.82-and 2.36-fold increases, respectively), whereas neither of these drugs is known to affect CYP1A2-cleared drugs (Naline et al, 1988;Konishi et al, 1994). However, in the present study it was shown that CYP2C19 and CYP3A4 also contribute to ramelteon metabolism.…”

Lack of effect of terfenadine on theophylline pharmacokinetics and metabolism in normal subjects.

“…In previous studies, the same protocol has disclosed pharmacokinetic interactions between theophylline and cimetidine or troleandomycin, and confirmed the absence of interaction with ketoconazole (Naline et al, 1988). This further validates the results obtained in the present study.…”

“…The aim of this study was to determine the effect of terfenadine treatment on plasma theophylline pharmacokinetics and also on theophylline metabolite formation since it has recently been shown that studies on the production and excretion of theophylline metabolites (3-methylxanthine, 1-methyluric acid and 1,3-dimethyluric acid) provide useful information for exploration of two of the oxidative pathways mediated by cytochrome P-450, (N-demethylation and 8-hydroxylation) (Campbell et al, 1987;Puurunen et al, 1980;Grygiel et al, 1984;Grygiel & Birkett, 1981;Naline et al, 1988. ) Correspondence: Dr E. Naline …”