Embryonic delivered dose of isotretinoin (13-cis-retinoic acid) and its metabolites in hamsters.
All-trans-retinoic acid (all-trans-RA) is required in normal embryogenesis and both deficiency and excess are teratogenic. Isotretinoin (13-cis-RA) is teratogenic in all species examined; based on administered dose, humans appear most sensitive, followed by (in order or decreasing sensitivity) monkey, rabbit, hamster, mouse, and rat. Identification of the teratogenic threshold in these species is difficult because RAs are normal physiologic constituents. The rabbit no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect-level (LOAEL) administered doses (3 and 15 mg/kg/day, respectively, on gestation Days 8-11) are less than the corresponding values in hamster (7.5 and 37.5 mg/kg/day, respectively, on gestation Days 7 and 8), but drawing conclusions from administered dose alone ignores differences in absorbed, metabolized, and embryonic delivered dose. Therefore, distribution and metabolism studies of 13-cis-RA at the NOAEL and LOAEL in pregnant hamsters were performed and plasma and tissue concentrations of parent compound and metabolites were compared to those found in rabbits. Metabolites of 13-cis-RA common to all species include three RAs (all-trans-RA, all-trans-4-oxoRA, 13-cis-4-oxoRA) and the glucuronide conjugate of 13-cis-RA (13-cis-RAG). As in rabbits, we found 13-cis-4-oxoRA also to be the major metabolite of 13-cis-RA in hamster plasma, peripheral tissues, and embryo. Of maternal tissues, peak 13-cis-RA concentrations were highest in liver. Total concentration of RA (13-cis-RA + 13-cis-4-oxoRA + all-trans-RA + all-trans-4-oxoRA) per gram of wet tissue was greatest in maternal liver, followed by that in lung, adipose tissue, muscle, kidney, and brain. At the NOAEL, total RA plasma Cmax in hamster was 6 times that in rabbit; at the LOAEL, hamster plasma total RA Cmax was 4 times that in rabbit. Hamster absorbed and metabolized dose (as AUC of plasma total RA) at the NOAEL and LOAEL was 2.6 and 2.4 times that in rabbit, respectively. In the embryo, hamster total RA Cmax was 2.7 times (at NOAEL) and 2.6 times (at LOAEL) that in rabbit. However, embryonic delivered dose (total RA AUC in hamster and rabbit embryo, respectively) at the NOAEL (2.08 and 2.14 microg . hr.g-1) and LOAEL (5.34 and 5.54 microg . hr . g-1) was virtually identical. Embryonic AUCs in hamster and rabbit for all-trans-RA and all-trans-4-oxoRA, metabolites which transactivate directly the nuclear RA receptors (RARs), were also very similar at the NOAEL (0.66 and 0.81 microg . hr g-1) and at the LOAEL (1.14 and 1.32 microg . hr g-1). Based on embryonic delivered dose, we suggest that 13-cis-RA is an equipotent teratogen in hamster and rabbit.
Eckhoff
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Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, New Jersey 07110, USA.
Willhite
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D000014:Abnormalities, Drug-Induced; D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D015474:Isotretinoin / Q000378:metabolism* / Q000633:toxicity; D011247:Pregnancy; D011817:Rabbits; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D013045:Species Specificity; D013723:Teratogens / Q000378:metabolism*
D018168:Receptors, Retinoic Acid; D013723:Teratogens; D015474:Isotretinoin