Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent, and indomethacin after oral administrations in rats

Abstract

Abstract N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M1) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M1 and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean Cmax (1·13 μg mL−1) of M1 after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean Cmax (3·38 μg mL−1) after 3 h in plasma. The mean AUC of M1 and indomethacin in plasma were 5·45 μg h mL−1 and 22·49 μg h mL−1, respectively. The mean tmax, Cmax and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/108 cells and 58·6 ng (164 pmol) h/108 cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/108 cells and 95·2 ng (266 pmol) h/108 cells, respectively. The PMNs/plasma ratio of M1 was about 2·8 times that of indomethacin. These results indicate that the association of M1, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.