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

N,N-Dimethylcarbamoylmethyl alpha,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, alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M(1)) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M(1) and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C-max (1.13 mu g mL(-1)) of M(1) after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C-max (3.38 mu g mL(-1)) after 3 h in plasma. The mean AUC of M(1) and indomethacin in plasma were 5.45 mu g h mL(-1) and 22.49 mu g h mL(-1), respectively. The mean t(max), C-max and AUC of M1 in PMNs were 1 h, 11.1 ng (41 pmol)/10(8) cells and 58.6 ng (164 pmol) h/10(8) cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15.4 ng (57 pmol)/10(8) cells and 95.2 ng (266 pmol) h/10(8) cells, respectively. The PMNs/plasma ratio of M(1) was about 2 8 times that of indomethacin. These results indicate that the association of M(1), an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.