Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl alpha,2-dimethyl-5H-[1]benzopyrano[2,3-b]- pyridine-7-acetate (Y-23023), a new prodrug type of anti-inflammatory 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 (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 micrograms mL-1) of M1 after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean Cmax (3.38 micrograms mL-1) after 3 h in plasma. The mean AUC of M1 and indomethacin in plasma were 5.45 micrograms h mL-1 and 22.49 micrograms h mL-1, respectively. The mean tmax, Cmax 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 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.
Yamada
I
I
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
Nagamatsu
Y
Y
Imayoshi
T
T
Shibata
M
M
Tsuji
A
A
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001578:Benzopyrans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D007213:Indomethacin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011485:Protein Binding; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D001798:Blood Proteins; D011355:Prodrugs; D011725:Pyridines; C063558:N,N-dimethylcarbamoylmethyl alpha,2-dimethyl-5H-1-benzopyrano(2,3-b)pyridine-7-acetate; D007213:Indomethacin