Abstract
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.
MeSH terms
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Administration, Oral
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Adrenergic Uptake Inhibitors / administration & dosage
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Adrenergic Uptake Inhibitors / blood
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Adrenergic Uptake Inhibitors / pharmacology
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Adrenergic alpha-Antagonists / administration & dosage
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Adrenergic alpha-Antagonists / blood
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Adrenergic alpha-Antagonists / pharmacology
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Adrenergic beta-Antagonists / administration & dosage
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Adrenergic beta-Antagonists / blood
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Adrenergic beta-Antagonists / pharmacology
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Animals
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Anti-Arrhythmia Agents / administration & dosage
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Anti-Arrhythmia Agents / blood
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Anti-Arrhythmia Agents / pharmacology
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Antibiotics, Antitubercular / administration & dosage
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Antibiotics, Antitubercular / blood
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Antibiotics, Antitubercular / pharmacology
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Blood Pressure / drug effects
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Calcium Channel Blockers / administration & dosage
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Calcium Channel Blockers / blood
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Calcium Channel Blockers / pharmacokinetics*
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Calcium Channel Blockers / pharmacology
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Cimetidine / administration & dosage
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Cimetidine / blood
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Cimetidine / pharmacology
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Dihydropyridines / administration & dosage
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Dihydropyridines / blood
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Dihydropyridines / pharmacokinetics*
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Drug Interactions
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Heart Rate / drug effects
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Histamine H2 Antagonists / administration & dosage
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Histamine H2 Antagonists / blood
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Histamine H2 Antagonists / pharmacology
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Male
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Methyldopa / administration & dosage
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Methyldopa / blood
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Methyldopa / pharmacology
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Prazosin / administration & dosage
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Prazosin / blood
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Prazosin / pharmacology
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Quinidine / administration & dosage
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Quinidine / blood
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Quinidine / pharmacology
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Rats
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Reserpine / administration & dosage
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Reserpine / blood
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Reserpine / pharmacology
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Rifampin / administration & dosage
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Rifampin / blood
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Rifampin / pharmacology
Substances
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Adrenergic Uptake Inhibitors
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Adrenergic alpha-Antagonists
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Adrenergic beta-Antagonists
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Anti-Arrhythmia Agents
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Antibiotics, Antitubercular
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Calcium Channel Blockers
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Dihydropyridines
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Histamine H2 Antagonists
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aranidipine
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Methyldopa
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Cimetidine
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Reserpine
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Quinidine
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Rifampin
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Prazosin