title: In vivo receptor occupancy and plasma concentration of pranidipine, a potent and long-acting dihydropyridine calcium antagonist.
abstract: The occupancy of 1,4-dihydropyridine (DHP) receptors by pranidipine was characterized in tissues of spontaneously hypertensive rats (SHR). Oral administration of pranidipine (1 and 3 mg/kg) in SHR produced significant (26-67%) decreases in the number of specific (+)-[(3)H]PN 200-110 binding sites (B(max)) with 2- to 4-fold increases in the apparent dissociation constant (K(d)) in myocardial tissues at 1, 3 and 6 h later. In these rats, there was a reduction (16-37%) of B(max) in cerebral cortical (+)-[(3)H]PN 200-110 binding. Occupancy of myocardial DHP receptors after oral administration of pranidipine correlated well with its plasma concentration. Oral administration of nifedipine (10 mg/kg) in SHR caused significant increase in K(d) values for (+)-[(3)H]PN 200-110 binding in myocardium and cerebral cortex at 1 h later. In vivo specific (+)-[(3)H]PN 200-110 binding in particulate fractions of SHR aorta was markedly (59-78%) reduced at 1, 3 and 12 h after oral administration of pranidipine (3 mg/kg), while myocardial (+)-[(3)H]PN 200-110 binding was decreased by 46-48% at 1 and 3 h later. In these rats, there was a significant decrease (34%) in cerebral cortical (+)-[(3)H]PN 200-110 binding at 3 h later. In contrast, nifedipine administration produced a similar degree of reduction (71-84%) of in vivo (+)-[(3)H]PN 200-110 binding in the myocardium, aorta and cerebral cortex. It is concluded that pranidipine may exert more selective and sustained occupation in vivo of DHP receptors in vascular tissues of SHR than in myocardial and brain tissues.
authors.affiliation: Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan. yamada@ys7.u-shizuoka-ken.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Uchida
authors.forename: A
authors.initials: A
authors.lastname: Urayama
authors.forename: R
authors.initials: R
authors.lastname: Kimura
mesh_terms: D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004095:Dihydropyridines / Q000097:blood / Q000493:pharmacokinetics*; D017275:Isradipine / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C048161:pranidipine; D009543:Nifedipine; D017275:Isradipine