Decreased absorption as a possible cause for the lower bioavailability of a sustained-release propranolol.
The influence of sustained absorption on the oral availability of propranolol (P) and the metabolic disposition of P were investigated by obtaining the partial metabolic clearances (CLm) following long-acting P (LA) dosing in comparison with the conventional propranolol tablet (CP). Ten healthy volunteers were given a single oral dose of an LA capsule (60 mg) and CP (20 mg x 3) using a crossover design. Blood and urine samples were collected over 24- and 48-h postdose periods, respectively. Concentrations of P, propranolol glucuronide (PG), 4-hydroxypropranolol (4P), 4-hydroxypropranolol glucuronide (4PG), 4-hydroxypropranolol sulfate (4PS), and naphthoxylactic acid (NLA) were determined by HPLC with fluorescence and UV detection. Significant differences were observed between LA and CP in the area under the plasma concentration-time curves (AUCs) for P, PG, and NLA and in the amounts excreted into urine (Ae) for all measured metabolites (i.e., PG, 4P, 4PG, 4PS, and NLA). The parallel decrease of the AUC for P and the excreted amounts of all measured metabolites following LA dosing resulted in partial metabolic clearances (CLm) and renal clearances (CL) for P and its metabolites that were similar to those observed for CP. Therefore, the hepatic metabolism of P would not be affected by the slower absorption at a single oral dose of 60 mg. These results indicate that the poor absorption of P from the gastrointestinal tract might be one of the factors causing the low bioavailability of P observed after administration of the sustained-release formulation.
Takahashi
H
H
Department of Biopharmaceutics, Meiji College of Pharmacy, Tokyo, Japan.
Ogata
H
H
Warabioka
R
R
Kashiwada
K
K
Ohira
M
M
Someya
K
K
D000328:Adult; D001682:Biological Availability; D002214:Capsules; D003692:Delayed-Action Preparations; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D010084:Oxidation-Reduction; D011433:Propranolol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility; D013431:Sulfates / Q000378:metabolism
D002214:Capsules; D003692:Delayed-Action Preparations; D005965:Glucuronates; D013431:Sulfates; C001422:4-hydroxypropranolol; D011433:Propranolol