Determination of enantiomeric concentrations of a 2,5-diaryltetrahydrofuran (L-668,750), a platelet-activating factor receptor antagonist, in rat plasma using a chiral alpha 1-acid glycoprotein high-performance liquid chromatographic column.
Racemic sulfonylated 2,5-diaryltetrahydrofuran [L-668,750, (+-)-trans-2-[3-methoxy-5-(2-hydroxy)ethylsulfonyl-4-n-propoxy]-p henyl-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran, I] is a potent, specific and orally active platelet-activating factor (PAF) receptor antagonist. Its (-)-(2S,5S) enantiomer [L-680,573, (S)-I] exhibited higher PAF antagonistic potency than the (+)-(2R,5R) enantiomer [L-680,574, (R)-I] in vitro and in animal models. For assay of drug concentrations in plasma of rats dosed intravenously or orally with tritium-labeled I, we have developed a high-performance liquid chromatographic (HPLC) method which directly resolved the two enantiomers. The column contained alpha 1-acid glycoprotein as the chiral stationary phase and was eluted with phosphate buffer, methanol and ethanol at neutral pH. The concentration of each enantiomer in the plasma was then determined by reverse isotope dilution assay. Results showed that the plasma clearance rate of the more potent (S)-I enantiomer was more than ten-fold faster than that of the (R)-I enantiomer; the enantioselective clearance resulted in nearly ten-fold higher concentrations of the latter in plasma at all time points regardless of the dosing route. This paper describes the HPLC chiral resolution method and its application in plasma analysis.
Alvaro
R F
RF
Department of Animal and Exploratory Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065.
Rosegay
A
A
Chiu
S H
SH
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation; D005663:Furans / Q000097:blood* / Q000494:pharmacology; D008297:Male; D009961:Orosomucoid / Q000737:chemistry*; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors*; D043562:Receptors, G-Protein-Coupled; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D005663:Furans; D009961:Orosomucoid; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C071469:MK 287