In vitro and in vivo biotransformation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-D]pyrimidine (U-89843) in the rat.
The biotransformation of 6,7-dimethyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo[2,3-d]pyrimidine (U-89843) has been studied in rat both in vitro and in vivo. Major metabolites observed by HPLC analysis of rat plasma, liver cytosol, and microsomal incubations were characterized by UV, LC/MS, and comparison with synthetic standards. The structures of the metabolites were shown to be the C-6 hydroxymethyl (U-97924), C-6 formyl (U-97865), and C-6 carboxyl analogs of U-89843. In the male rat, formation of U-97924 is mediated by cytochrome P4502C11. Kinetic analysis of U-97924 formation indicated that it was a high-affinity/high-capacity process (KM = 4.2 +/- 0.5 microM; Vmax = 21.2 +/- 0.8 nmol/mg/min). Formation of U-97865 via enzymatic oxidation from the primary metabolite U-97924 was catalyzed by both the microsomal subcellular fraction in a NADPH-dependent process (presumably via cytochrome P450) and in cytosol by NAD(+)-dependent alcohol dehydrogenase. Upon incubation with cytosolic fractions, U-97865 was found to undergo NAD(+)-dependent oxidation, mediated by aldehyde dehydrogenase, to the corresponding carboxylic acid. Although significant levels of U-89843, U-97924, and U-97865 were observed in vivo in rat plasma, only a minor amount of the carboxylic acid together with larger amounts of unidentified polar metabolites were excreted in urine and feces.
Zhao
Z
Z
Metabolism Research, Upjohn Company, Kalamazoo, MI 49001, USA.
Koeplinger
K A
KA
Bundy
G L
GL
Banitt
L S
LS
Padbury
G E
GE
Hauer
M J
MJ
Sanders
P E
PE
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet
D000975:Antioxidants; D011743:Pyrimidines; D011758:Pyrroles; C097295:U 89843