Plasma pharmacokinetics and metabolism of 13-cis- and all-trans-retinoic acid in the cynomolgus monkey and the identification of 13-cis- and all-trans-retinoyl-beta-glucuronides. A comparison to one human case study with isotretinoin.
In order to compare the disposition and metabolism of 13-cis-retinoic acid (13-cis-RA) and all-trans-retinoic acid (all-trans-RA) in the nonpregnant female cynomolgus monkey, the plasma concentrations of the parent compound, the oxidized metabolites 4-oxo-13-cis-retinoic acid and 4-oxo-all-trans-retinoic acid, and the conjugate metabolites 13-cis-retinoyl-beta-glucuronide (13-cis-RAG) and all trans-retinoyl-beta-glucuronide (all-trans-RAG), were determined on day 1 and day 10 after oral dosing of 2 and 10 mg 13-cis- and all-trans-RA/kg/day. Both 13-cis-RAG and all-trans-RAG have been identified as major plasma metabolites in these studies using thermospray/HPLC/mass-spectrometry of the intact conjugates. AUC comparisons from 0-24 hr after administration indicated that 13-cis-RA treatment resulted in primarily cis metabolites and all-trans-RA treatment resulted in primarily trans metabolites, although low levels of isomerization products were observed. Comparison of the two doses (2 and 10 mg/kg, po) revealed that the AUCs were proportional to the dose administered. Although qualitatively similar, elimination of 13-cis-RA in the monkey was more rapid than in the human, and approximately a 10-fold greater dose of 13-cis-RA was required in the monkey to produce the AUC values comparable to the human. The elimination of all-trans-RA in monkey was faster than that of 13-cis-RA and tended to increase with repeated dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
Institute of Toxicology and Embryopharmacology, Free University Berlin, F.R.G.
J C
JC
Kraft
W
W
Slikker
J R
JR
Bailey
L G
LG
Roberts
B
B
Fischer
W
W
Wittfoht
H
H
Nau
D000818:Animals; D005260:Female; D005966:Glucuronidase; D006801:Humans; D015474:Isotretinoin / Q000378:metabolism; D008252:Macaca fascicularis; D013058:Mass Spectrometry; D013237:Stereoisomerism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
C026787:retinoyl glucuronide; D014212:Tretinoin; D005966:Glucuronidase; D015474:Isotretinoin