Use of a carrier for quantitation of a new dihydropyridine calcium antagonist (OPC-13340) in human plasma by highly sensitive gas chromatography with negative-ion chemical ionization mass spectrometry.
A sensitive gas chromatographic-mass spectrometric method for the quantitation of (+/-)-methyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (OPC-13340, I), a new dihydropyridine calcium antagonist with a potent and long-acting antihypertensive and antianginal effect, was developed in order to elucidate its pharmacokinetics. Dihydropyridine calcium antagonist have been usually quantifed by this technique in the negative-ion chemical ionization mode. However, direct application of this method to quantify trace amounts of I in biological fluids completely failed, owing to its adsorption on the column and oxidation of its dihydropyridine ring. Human plasma containing I and (+/-)-[2H3]methyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (II), the internal standard, was extracted with n-hexane-diethyl ether under weakly basic conditions (pH 8). In order to prevent adsorption of the compounds on the column, (+/-)-[2H5]ethyl 3-phenyl-2(E)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (III), an analogue of I, was added to the extracts as a carrier. In addition, this carrier was also effective in preventing the oxidation of I. The quantitation limit of I in human plasma by this method was found to be less than 30 pg/ml. Thus, the method is sufficiently sensitive to study the pharmacokinetics of I in humans.
Nagasawa
M
M
Tokushima Research Institute, Otsuka Pharmaceutical Co. Ltd., Japan.
Sasabe
H
H
Shimizu
T
T
Mori
H
H
D002121:Calcium Channel Blockers / Q000097:blood*; D004095:Dihydropyridines / Q000097:blood*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D010084:Oxidation-Reduction; D012016:Reference Values
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C048161:pranidipine