Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog.
The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.
Midgley
I
I
Department of Drug Metabolism, Huntingdon Life Sciences Ltd, Huntingdon, UK. MidgleyI@ukorg.Huntingdon.com
Fitzpatrick
K
K
Wright
S J
SJ
John
B A
BA
Peard
A J
AJ
Major
R M
RM
Holding
J D
JD
McBurney
A
A
Anacardio
R
R
Novellini
R
R
Ferrari
M P
MP
D000818:Animals; D001711:Biotransformation; D002247:Carbon Isotopes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D010084:Oxidation-Reduction; D010949:Plasma / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine
D002247:Carbon Isotopes; D019743:Chemokines, CXC; D013449:Sulfonamides; C490707:reparixin