Interaction of some drugs on the pharmacokinetics or pharmacodynamics of MPC-1304, a dihydropyridine Ca2+ antagonist.
The aim of this study was to assess the pharmacokinetics and subsequent pharmacodynamic interaction of MPC-1304, a dihydropyridine Ca2+ antagonist, with other drugs in animal experiments. We measured the systolic blood pressure and heart rate of conscious spontaneously hypertensive rats implanted with battery-operated biotelemetry devices after combined administration of various drugs. Cimetidine (10 mg/kg) did not affect the reduction in systolic blood pressure and the increase in heart rate induced by MPC-1304, whereas it significantly increased the plasma concentration of a metabolite of MPC-1304 (M-1) compared to that detected when MPC-1304 was administered alone. When MPC-1304 was consecutively administered in combination with rifampicin (400 mg/kg) for 9 days, the plasma concentrations of MPC-1304 and of M-1 significantly decreased compared to those found when MPC-1304 alone was given. In spite of these reductions in plasma concentrations, rifampicin did not attenuate the hypotensive action induced by MPC-1304. When prazosin, reserpine, or methyldopa was administered in combination with MPC-1304, the hypotensive action was enhanced as compared to that by MPC-1304 alone or to that by the co-administered drug used alone (prazosin, reserpine, or methyldopa). Quinidine (10 mg/kg) affected neither the hypotensive action induced by MPC-1304 nor the plasma concentrations of MPC-1304 and M-1. These results indicate that cimetidine and rifampicin interact with MPC-1304 pharmacokinetically, without apparently changing the hypotensive action of MPC-1304, whereas quinidine does not affect the metabolism of MPC-1304, and that other hypotensive drugs, such as prazosin, reserpine, and methyldopa, potentiate the hypotensive action of MPC-1304.
Nakano
M
M
Pharmacology Research Laboratory, Taiho Pharmaceutical Co., Tokushima, Japan.
Miyoshi
K
K
Umeno
Y
Y
Yoshida
K
K
Nishizaki
J
J
Miyake
H
H
D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002927:Cimetidine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D004095:Dihydropyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D008297:Male; D008750:Methyldopa / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D011224:Prazosin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D011802:Quinidine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D051381:Rats; D012110:Reserpine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D012293:Rifampin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D000904:Antibiotics, Antitubercular; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D006635:Histamine H2 Antagonists; C059427:aranidipine; D008750:Methyldopa; D002927:Cimetidine; D012110:Reserpine; D011802:Quinidine; D012293:Rifampin; D011224:Prazosin