Metabolism and Pharmacokinetics of 1-(2'-hydroxy-ethyl)- and 1-(3'-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-ones in the Rat

The urinary recovery (p.o.) and pharmacokinetics (i.v. and p.o.) of two compounds from the 1-hydroxyalkyl-3-hydroxypyridin-4-one series. 1-(2'-hydroxyethyl)-2-ethyl-3-hydroxypyridine-4-one (CP102) and 1-(3'-hydroxypropyl)-2-ethyl-3-hydroxypyridin-4-one (CP106) were studied in the rat. The pharmacokinetics of the 1-carboxyethyl metabolite (CP110) of CP106 was also studied (i.v.). CP102 was not metabolised to any considerable extent with 68.4 +/- 12.2% of the administered dose recovered unchanged in rat urine. In contrast, CP106 undergoes extensive phase I metabolism to form the 1-carboxyalkyl metabolite which accounted for 56.4 +/- 11% of the administered dose with 22.0 +/- 1.0% as unchanged drug. Intravenous and oral pharmacokinetics of CP102 and CP106 were studied in the rat at 450 mumols/kg. The AUCs of CP102 and CP106 after bolus i.v. infusion were 458 +/- 38 and 171 +/- 20 mumols/l.h. The AUC values after bolus oral administration were 318 +/- 46 and 77 +/- 18 mumols/l.h, respectively, with corresponding bioavailabilities (F) of 0.69 and 0.45. The Cmax of CP102 and CP106 were 142 +/- 25 and 70 +/- 15 mumols/l with Tmax values of 0.75 +/- 0.15 and 0.50 +/- 0.10 h, respectively. The CL, MRT and Vdss of CP102 was 1.00 +/- 0.09 l/kg/h, 0.92 +/- 0.04 h and 0.91 +/- 0.05 l/kg, respectively. The corresponding pharmacokinetic parameters for CP106 were 2.64 +/- 0.20 l/kg/h, 0.42 +/- 0.12 h and 1.12 +/- 0.26 l/kg, respectively. Renal clearance (CLR) of CP102 and CP106 were 1.00 +/- 0.18 l/kg and 1.27 +/- 0.31 l/kg respectively. The pharmacokinetics of CP110, which was conducted by the i.v. route only at a dose of 450 mumols/kg, had an AUC of 289 +/- 46 mumols/l.h, CL of 1.56 +/- 0.29 l/kg/h, MRT of 0.25 +/- 0.09 h and Vdss of 0.40 +/- 0.13 l/kg, respectively.