Influence of Propiverine on Hepatic Microsomal Cytochrome P450 Enzymes in Male Rats

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT: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 ␤-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.The benzilic acid derivative, propiverine 1 [(2,2-diphenyl-2(1-propoxy) acetic acid (1-methylpiperid-4-yl) ester] (MICTONORM, Apogepha, Dresden), has been shown in controlled clinical trials to be effective in the treatment of children, adults, and elderly suffering from detrusor hyperreflexia and symptoms of an overactive bladder. Pharmacodynamic investigations showed anticholinergic and additional effects on calcium influx and calcium homeostasis in urinary bladder preparations, thus proving the dual mode of action of propiverine in relaxing detrusor smooth muscle. The drug is rapidly absorbed from the gastrointestinal tract, widely distributed, and highly bound to plasma proteins. Incomplete oral bioavailability is mainly caused by intensive first-pass metabolism. Propiverine undergoes N-oxidation of the piperidine moiety and dealkylation of the propyl side chain by enzymes of the hepatic microsomal drug-oxidizing system (for review, Madersbacher and Mürtz, 2001).There is evidence from former animal studies that propiverine at higher doses increases the content of cytochrome P450 (P450) and the activities of aniline hydroxylase and aminopyrine demethylase in rat liver (Borchert et al., 1986;Wengler et al., 1989;Yamashita et al., 1990). Since most patients suffering from symptoms of overactive bladder are over 60 years and consumers of two and more concomitant drugs, information on potential enzyme-inducing or -inhibiting properties of a drug, which is subjected for chronic treatment, is required from studies in animals and man. Therefore, the influence of repeated oral administration of propiverine on the most important hepatic microsomal P450-dependent monooxygenases was measured in rats to evaluate its influence on...

Effect of propiverine on cytochrome P450 enzymes: a cocktail interaction study in healthy volunteers

“…Based on the paraxanthine/caffeine plasma ratio 6 h postdose, which is extensively validated for assessment of CYP1A2 activity (Fuhr et al, 1996;Streetman et al, 2000a), we found no inducing (or inhibitory) effect of chronic treatment with propiverine on the CYP1A2 function, indicating that the characterization of propiverine as a phenobarbital-type inducer at high doses in animals (Walter et al, 2003) is not predictive for an effect of therapeutic propiverine doses on CYP1A2 in humans.…”

“…If the study showed pronounced inhibition of these enzymes, indicating high propiverine concentrations at hepatic P450 binding sites, which might result in relevant in vivo effects on enzymes for which propiverine had only a minor effect in vitro, effects on CYP1A2 and CYP2D6 activity were to be evaluated additionally. Although there was no such pronounced inhibition, propiverine effects on CYP1A2 were also evaluated, prompted by recent additional data (Walter et al, 2003). We also decided to evaluate the effects on CYP2D6, but these results will be reported separately because extensive additional evaluations are required to assess the validity of dextromethorphan metabolic ratios in urine and plasma for the quantification of drug-drug interactions (Streetman et al, 2000a;Ö zdemir et al, 2004;Borges et al, 2005).…”

“…In preliminary studies in human liver microsomes, propiverine showed competitive inhibition of CYP2D6 with K i values more than 30-fold above propiverine plasma peak concentrations (APOGEPHA, data on file). Recently, Walter et al (2003) reported that the drug administered in rats in doses about 100 times above the therapeutic doses in humans is a phenobarbitaltype enzyme inducer. In summary, propiverine appears to interact with P450s mainly as a substrate.…”

Investigation of the in Vitro Metabolism of the Analgesic Flupirtine

“…Rat liver microsomes and S9 fractions were prepared by standard procedures (Walter et al, 2003) and stored at Ϫ32°C. The human liver microsomes and S9 fractions were purchased from In Vitro Technologies, Inc. (Baltimore, MD) and stored at Ϫ70°C.…”

“…Microsomes from noninduced and from dexamethasone-, rifampicin-, phenobarbital-, and ␤-naphthoflavone-induced rat livers were used (Walter et al, 2003). The NADPH-regenerating system and NADPH negative controls were incubated for 5 min at 37°C in open tubes.…”