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.
Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, NC 27709.
J L
JL
Woolley
D V
DV
Deangelis
M E
ME
Grace
S H
SH
Liao
R C
RC
Crouch
C W
CW
Sigel
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