title: Influence of a fat-rich meal on bioavailability of extended-release and immediate-release propiverine.
abstract: The muscarinic receptor antagonist propiverine is unique insofar as extended-release (ER) tablets are of higher bioavailability than immediate-release (IR) tablets; this is caused by lower "first-pass" elimination of propiverine via CYP3A4 and efflux transporters in the distal small intestine and colon. Food may influence gastrointestinal transiting and, in turn, may affect regional absorption of propiverine IR and ER. Therefore, food effects on disposition of 30 mg IR and 45 mg ER were measured in a randomized, open, 4-period interaction study in 24 healthy participants. In fasting participants, ER had higher bioavailability than IR (F(rel) = 169%, P = .03). Fat-rich meal did not change the disposition of ER markedly (AUC(0-∞) ratio, 1.00 [90% confidence interval (CI), 0.90-1.11], C(max) ratio, 0.97 [0.87-1.09]). However, C(max) and renal A(e) of the major N-oxidized metabolite (M-5) significantly increased, whereas t(1/2) decreased. By eating a fat-rich meal before administration, the differences in absorption of IR and ER were nearly abolished (AUC(0-∞) ratio for propiverine, 1.12 [90% CI, 0.95-1.33]; AUC(0-∞) ratio for M-5, 0.89 [0.82-0.95]). In conclusion, propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates.
authors.affiliation: Department of Clinical Pharmacology, Ernst Moritz Arndt University, Friedrich-Loeffler-Str. 23d, D-17487 Greifswald, Germany. siegmuw@uni-greifswald.de
authors.forename: Werner
authors.initials: W
authors.lastname: Siegmund
authors.forename: Joachim
authors.initials: J
authors.lastname: Siegert
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.forename: Frieder
authors.initials: F
authors.lastname: Schnabel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Feustel
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kirch
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001561:Benzilates / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004041:Dietary Fats / Q000008:administration & dosage*; D005215:Fasting / Q000097:blood; D005260:Female; D018565:Food-Drug Interactions; D005858:Germany; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D010084:Oxidation-Reduction; D019518:Postprandial Period; D055815:Young Adult
chemical_list: D001561:Benzilates; D003692:Delayed-Action Preparations; D004041:Dietary Fats; D018727:Muscarinic Antagonists; C015586:propiverine