METABOLISM AND PHARMACOKINETICS OF METHYLACETOXYETHYL)-2-ETHYL-3-HYDROXYPYRIDIN-4-ONE (CP117) IN THE RAT

Metabolism and pharmacokinetics of methylacetoxyethyl)-2-ethyl-3-hydro xypyridin-4-one (CP117) were studied in the rat. Urinary recovery stud ies were conducted in normal (oral and intravenous) and iron-overloade d rats (500 mg Fe/kg body weight; oral only). In normal rats, the majo rity of the dose recovered in the urine was as the hydrophilic metabol ite, CP102, accounting for 69.7 +/- 9.4% (oral) and 80.7 +/- 7.9% (int ravenous) of the administered dose, There was, however, a dramatic dec rease in the amount of CP102 recovered (47.7 +/- 5.9%) (p less than or equal to 0.05) in the iron-loaded group of animals. The amount of CP1 02 glucuronide conjugate recovered in the normal and iron-overloaded r ats after oral administration of CP117 did not differ significantly wi th values of 6.5 +/- 2.5% and 7.1 +/- 2.5%, respectively. There was, h owever, a significant increase in CP102 glucuronide conjugate (13.7 +/ - 3.0%) (p less than or equal to 0.05) after intravenous administratio n of CP117, Urinary iron content was determined in the iron-overloaded and normal (oral) animals. Negligible levels of the CP117 iron comple x and only 0.6 +/- 0.2% was present as the corresponding CP102 complex in the urine of normal animals, Less than 0.1% of the administered do se was recovered as CP117-iron complex and only 1.3 +/- 0.2% as CP102- iron complex in the iron-overloaded animals. Total recovery of the adm inistered dose was significantly different between normal (po) and iro n-overloaded groups of animals, decreasing from 76.4 +/- 11.7% to 57.2 +/- 9.6%, respectively (p less than or equal to 0.05). There was no s ignificant difference between the two routes of administration in norm al animals, with total recovery of the administered dose of CP117 bein g 96.1 +/- 9.1% by the intravenous route, Intravenous and oral pharmac okinetics of CP117 was studied in the rat at a fixed dose of 450 mu mo l/kg. The AUC of the drug was 43.2 +/- 9.1 mu mol/liter . hr and 4.1 /- 1.8 mu mol/liter . hr via the intravenous and oral routes, respecti vely, thus indicating that the systemic bioavailability of the drug is < 10%. Pharmacokinetic parameters of the drug determined by the Intra venous route indicate that CP117 has a plasma clearance of 10.9 +/- 3. 0 mu mol/liter . hr, a mean residence time of 0.14 +/- 0.05 hr, and vo lume of distribution at steady-state of 1.54 +/- 0.52 liters . kg(-1). The C-max and t(max) of CP117 were 12.1 +/- 2.5 mu mol/liter and 7.0 +/- 2.7 min, respectively, The AUC of the main metabolite, CP102, decr eased from 425.3 +/- 8.5 mu mol/liter . hr to 282 +/- 31 pmol/liter . hr via the intravenous and oral routes, which is presumed to reflect d ifferences in hepatic extraction and routes of elimination of the drug . Parallel absorption studies conducted using the in situ isolated rat gut loop model indicate that the majority of the administered dose wa s absorbed intact as the parent drug with mesenteric vein AUC values o f 3.1 +/- 1.7 mmol/liter . hr and 0.3 +/- 0.04 mmol/liter . hr for CP1 17 and CP102, respectively.