Pharmacokinetics and safety of propiverine in patients with fatty liver disease

Siepmann, Martin; Nokhodian, A.; Thümmler, D.; Kirch, Wilhelm

doi:10.1007/s002280050549

Cited by 17 publications

(12 citation statements)

References 11 publications

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“…The exposure of propiverine and its main metabolite, propiverine-N-oxide, at steady state during the test period is in agreement with published data (Siepmann et al, 1998). The selected dosing scheme has been shown to be therapeutically effective and is used clinically (Alloussi et al, 2005).…”

Section: Discussionsupporting

confidence: 85%

“…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).…”

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confidence: 99%

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Effect of Propiverine on Cytochrome P450 Enzymes: A Cocktail Interaction Study in Healthy Volunteers

Tomalik-Scharte

Jetter²,

Kinzig‐Schippers³

et al. 2005

Drug Metabolism and Disposition

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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

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

Effect of Propiverine on Cytochrome P450 Enzymes: A Cocktail Interaction Study in Healthy Volunteers

Tomalik-Scharte

Jetter²,

Kinzig‐Schippers³

et al. 2005

Drug Metabolism and Disposition

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“…This finding is consistent with the results reported for the extraction of other compounds in human and rat NASH livers. For instance, silymarin has a significantly increased area under the curve in human NASH (Schrieber et al, 2008), whereas propiverine has a small but insignificant change (Siepmann et al, 1998). We have shown that palmitate E is lower in NASH rat livers (Hung et al, 2005).…”

Section: Discussionmentioning

confidence: 64%

“…Lickteig et al (2007) showed increases in liver transporter mRNA and protein levels as well as a decreased biliary excretion of acetaminophen conjugates in rats fed a methio-nine-and choline-deficient diet for 8 weeks. Pharmacokinetic studies in NASH patients and the NASH rat model have shown a significant decrease in the hepatic extraction (E) ratio (Siepmann et al, 1998;Hung et al, 2005;Schrieber et al, 2008). However, the actual effects of steatosis, necroinflammation, and damaged microcirculation in the NASH liver on the individual hepatic pharmacokinetic processes have not, as yet, been well addressed.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Pharmacokinetics of Cationic Drugs in a High-Fat Emulsion-Induced Rat Model of Nonalcoholic Steatohepatitis

Robertson¹,

Thorling²,

Zhang³

et al. 2011

Drug Metabolism and Disposition

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ABSTRACT:The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL int ) and permeability-surface area product (PS) with pK a defining the extent of sequestration in the liver [apparent distribution ratio (K v )]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K v , and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL int in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K v , CL int , and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK a ) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.

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“…These data obtained from in vitro studies were in accordance with the results of our functional in vivo study. Furthermore, it is known that the free plasma concentration is higher for P4NO than for P4 [15] , and therefore anticholinergic effects should be less pronounced compared to P4.…”

Section: Discussionmentioning

confidence: 99%

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

Scheepe¹,

Braun²,

Jünemann³

et al. 2008

Urol Int

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Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects. Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively. Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure. Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

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Pharmacokinetics and safety of propiverine in patients with fatty liver disease

Abstract: No pharmacokinetic differences relevant for safety were observed, comparing patients with and without fatty liver disease following repeated oral administration of propiverine. Thus there seems to be no need to adjust the dose in patients with mild to moderate impairment of liver function.

Cited by 17 publications

References 11 publications

Effect of Propiverine on Cytochrome P450 Enzymes: A Cocktail Interaction Study in Healthy Volunteers

Effect of Propiverine on Cytochrome P450 Enzymes: A Cocktail Interaction Study in Healthy Volunteers

Hepatic Pharmacokinetics of Cationic Drugs in a High-Fat Emulsion-Induced Rat Model of Nonalcoholic Steatohepatitis

Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

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