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

Abstract

ABSTRACT:The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam Propiverine hydrochloride, described below as propiverine, is indicated for the treatment of urinary incontinence, as well as urinary urgency and frequency in patients who have either idiopathic detrusor overactivity (overactive bladder) or neurogenic detrusor overactivity (detrusor hyperreflexia) from spinal cord injuries, e.g., transverse lesion paraplegia. It exhibits antagonistic effects toward muscarinic acetylcholine receptors and calcium channel-modulating properties (Siegmund et al., 1990;Yono et al., 1999;Madersbacher and Mürtz, 2001).After oral administration, propiverine is rapidly and almost completely absorbed from the gastrointestinal tract. The maximal serum concentration is reached approximately 90 min after a single dose of 15 mg. Propiverine undergoes extensive presystemic metabolism via N-oxidation to propiverine-N-oxide with involvement of cytochrome P450 enzymes. Mean elimination half-life after chronic administration of propiverine is about 15 h. The major fraction of propiverine and its metabolites is eliminated in the urine (Haustein and Hüller, 1988;Siepmann et al., 1998). Information on the enzymes mediating phase I metabolism of propiverine has been obtained in several in vitro systems (APOGEPHA, data on file). The primary metabolic route involves the oxidation of the piperidyl-N and is mediated by CYP3A4 and flavin-containing monoxygenases 1 and 3, and leads to the formation of the much less active N-oxide. CYP2C9 and CYP2C19 may also mediate a fraction of overall propiverine elimination, whereas other enzymes (e.g., CYP1A2 and CYP2D6) were involved to a minor extent.Several studies concerning possible drug-drug interactions of propiverine have been published. Müller et al. (1993) demonstrated that there is no effect of the CYP2D6 genotype on propiverine biotransformation in humans, so that no effect of CYP2D6 inhibitors on propiverine pharmacokinetics is expected. Results of a study performed in rats provided no evidence for propiverine to cause relevant drug-drug interactions (Borchert et al., 1986). Studies on the effect of propiverine on drug-metabolizing enzymes in human and rat hepatocyte cultures demonstrated an increase in CYP3A4 mRNA and This study was supported by APOGEPHA Arzneimittel GmbH, Dresden, Germany.Article, publication date, and citation information can be found at

No role for the CYP3A5*3 polymorphism in intestinal and hepatic metabolism of midazolam

“…Total clearance (Cl) and intestinal availability (Fi) of midazolam, used as metrics of hepatic and intestinal CYP3A activity, respectively, were assessed by population analysis using NONMEM software (V version 1.1, NONMEM Project Group, University of California at San Francisco, 1998). A two compartment model gave the best fit allowing for determination of Cl and oral bioavailability, whereas for calculation of Fi an additional equation was implemented [3].…”

Pharmacokinetic assessment of a five‐probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A

“…This approach was successfully used to investigate the effect of drugs on various CYP isoforms (e.g. the effect of propiverine on the activity of intestinal 3A and of hepatic CYP3A, CYP2C9, CYP2C19 and CYP1A2 [3]). …”

Assessment of urinary mephenytoin metrics to phenotype for CYP2C19 and CYP2B6 activity

“…The procedures of these studies has already been described in more detail. 11,28 The primary phenotyping objectives of study C with regard to mephenytoin were the generation of confirmatory data for variability and selectivity evaluations of the CYP2C19 metrics as well as a more thorough characterization of the slow nirvanol excretion. In this study, urine was collected in-house until 48 hours postdose and completed by two additional overnight in-house urine collection periods from 86-94 and 158-166 hours postdose.…”

“…11,12 Omeprazole and proguanil are used as alternative probe drugs for CYP2C19 phenotyping. But, in addition to CYP2C19 mediated hydroxylation, CYP3A4 mediated sulfoxidation of both omeprazole and 5-hydroxyomeprazole, the metabolite formed by CYP2C19, occurs.…”