The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.
The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.
Woolley
J L
JL
Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
Deangelis
D V
DV
Grace
M E
ME
Liao
S H
SH
Crouch
R C
RC
Sigel
C W
CW
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001682:Biological Availability; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D005243:Feces / Q000737:chemistry; D007275:Injections, Intravenous; D008297:Male; D011725:Pyridines / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D013762:Tetrahydrofolate Dehydrogenase / Q000097:blood
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D011725:Pyridines; D011743:Pyrimidines; C073779:2'-demethylpiritrexim; C073780:5'-demethylpiritrexim; D013762:Tetrahydrofolate Dehydrogenase; C024530:piritrexim