Influence of propiverine on hepatic microsomal cytochrome p450 enzymes in male rats.
The bladder spasmolytics propiverine was shown to induce hepatic cytochrome P450 (P450) and aminopyrine and aniline oxidation in rats. To characterize the type of enzyme induction and its dose dependence, activities of seven hepatic microsomal P450-dependent monooxygenases were measured in 72 male LEW1A albino rats (body weight 236-295 g) after oral treatment with 0.5, 2, 6, and 60 mg/kg of propiverine hydrochloride for 5 days and compared with the effects of 40 mg/kg beta-naphthoflavone, 10 mg/kg phenobarbital, and 20 mg/kg dexamethasone (each group, n = 8). CYP2B expression was measured by Western blotting. Furthermore, the inhibitory potency of propiverine on P450 enzymes was evaluated in competition assays with three most specific monooxygenases. Results show that Propiverine induced several monooxygenases and CYP2B expression dose dependently. The effects were well comparable with a phenobarbital-type inducer with 60 mg/kg being equipotent to 10 mg/kg phenobarbital. Furthermore, propiverine in low concentrations inhibited pentylresorufin O-dealkylase (for CYP2B) in vitro. In conclusion, propiverine is a phenobarbital-type inducer on hepatic P450 enzymes in rats in doses about 100-times above the therapeutic doses in man.
Walter
R
R
Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich Loefflerstr. 23 d, D-17487 Greifswald, Germany.
Ullmann
C
C
Thummler
D
D
Siegmund
W
W
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001561:Benzilates / Q000494:pharmacology*; D015153:Blotting, Western; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001561:Benzilates; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; C015586:propiverine; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D010634:Phenobarbital