The dispositional enantioselectivity of indobufen in rat and mouse.
The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen, a novel platelet aggregation inhibitor, have been studied in rats and mice given either the racemic compound or the individual enantiomers (rat 8 mg/kg racemate, 4 mg/kg enantiomers; mouse 25 mg/kg racemate, 12.5 mg/kg enantiomers). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. In rat, the two enantiomers have very different plasma elimination half lives (S, 3.9 hr; R, 12.2 hr), irrespective of the optical form administered. The plasma concentration-time curves of S-indobufen were identical after racemic or S-indobufen, but the plasma levels of R-indobufen were lower after the R-enantiomer than after the racemate. Urinary recovery of free and conjugated indobufen was less than 3% of the dose, independent of the optical form administered. In the mouse, R-indobufen was cleared from plasma more rapidly than its S-antipode (elimination T1/2 R, 2.5 hr; S, 3.8 hr) but differences were smaller than those seen in the rat. The plasma concentration-time curves of the S-enantiomer were the same after racemic or S-indobufen, but levels of its R-antipode were much lower when it was given alone than after administration of the racemate. The urinary recovery of free and conjugated indobufen also exhibited enantioselectivity, with preferential elimination of the S-enantiomer.
Strolin Benedetti
M
M
Research and Development, Farmitalia Carlo Erba-Erbamont Group, Milan, Italy.
Moro
E
E
Frigerio
E
E
Jannuzzo
M G
MG
Roncucci
R
R
Caldwell
J
J
D000818:Animals; D005260:Female; D006207:Half-Life; D054833:Isoindoles; D008657:Metabolic Clearance Rate; D051379:Mice; D010654:Phenylbutyrates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D054833:Isoindoles; D010654:Phenylbutyrates; D010975:Platelet Aggregation Inhibitors; C020371:indobufen