Determination of plasma concentrations of SCH 44643 by a GC method and correlation of plasma concentration and anti-PAF activity in cynomolgus monkeys.
Inhibiting the action of platelet-activating factor (PAF) is a new therapeutic approach for the treatment of allergic disorders. SCH 44643 is a new orally-active antagonist of response to both PAF and histamine. This study was done to determine plasma drug concentrations using a GC method and to compare them to ex-vivo anti-PAF activity in the plasma of cynomolgus monkeys following a single oral (12.5 mg kg-1) administration. The GC method involved organic solvent extraction of monkey plasma followed by a GC analysis in a RTX-1 capillary column with a nitrogen/phosphorus detector. The method showed good precision (RSD < 8%) and accuracy (bias < 9%) with a limit of quantitation of 20 ng ml-1. The plasma profiles of SCH 44643 concentration and anti-PAF activity were very similar in each of the six monkeys. There was an excellent correlation (r = 0.9003) between anti-PAF activity and plasma concentration of SCH 44643, suggesting that the anti-PAF activity in cynomolgus monkeys was primarily due to unchanged SCH 44643, rather than its potential metabolite(s).
Lin
C C
CC
Department of Drug and Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Billah
M
M
Kim
H K
HK
Egan
R
R
Anthes
J
J
Gilchrest
H
H
Cayen
M
M
D000284:Administration, Oral; D000818:Animals; D002850:Chromatography, Gel; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis / Q000097:blood*; D008297:Male; D010879:Piperazines / Q000097:blood*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*
D010879:Piperazines; D010972:Platelet Activating Factor; C105629:Sch 44643