Distribution, teratogenicity, and embryonic delivered dose of retinoid Ro 23-9223.
Ro 23-9223 is a highly lipophilic aromatic retinoid with antiproliferative and sebum supressive effects in preclinical disease models of acne. To investigate the relation between Ro 23-9223 developmental toxicity, drug distribution, and transplacental transfer, groups of pregnant hamsters were given oral doses of 50-500 mg/kg Ro 23-9223 on days 8 and 9 of gestation. The teratogenic phenotype induced at doses greater than 125 mg/kg per day was similar to that found after exposure to doses of 13-cis-retinoic acid (isotretinoin, Accutane) greater than 37.5 mg/kg per day. Oral bioavailability of Ro 23-9223 was very low compared to 13-cis-retinoic acid. The highest concentrations of Ro 23-9223 were found in maternal liver, lung, adipose tissue, cardiac muscle, and placenta, whereas only little of the compound crossed the blood-brain barrier. Based on embryo AUC, Ro 23-9223 had a 30- to 50-fold greater embryo:maternal concentration ratio than 13-cis-retinoic acid plus its bioactive metabolites following similar doses of the two retinoids. In preclinical pharmacology studies, oral doses of Ro 23-9223 (5 mg/kg per day) and 13-cis-retinoic acid (10 mg/kg per day) produced comparable gland size reductions in the hamster ear sebaceous gland reduction assay. Under these conditions, Ro 23-9223 plasma AUC was 40 times smaller than that of 13-cis-retinoic acid plus its bioactive metabolites. Assuming that the near linear dose-exposure relationship of Ro 23-9223 extends beyond the dose range of this study, embryo AUCs of Ro 23-9223 and 13-cis-retinoic acid (plus metabolites) would be near identical following pharmacologically equivalent doses. A comparison of embryo retinoid AUCs suggests a 4-fold lower teratogenic potency of Ro 23-9223 compared to with 13-cis-retinoic acid. Despite high embryo levels in hamsters, the data suggest an improved therapeutic index for Ro 23-9223 compared with 13-cis-retinoic acid in a preclinical acne disease model.
Willhite
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State of California, 700 Heinz Street, Suite 200, Berkeley, California 94710, USA.
Lovey
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Eckhoff
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D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D015474:Isotretinoin / Q000633:toxicity*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D012176:Retinoids / Q000493:pharmacokinetics* / Q000633:toxicity*; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
D012176:Retinoids; C408022:Ro 23-9223; D013723:Teratogens; D015474:Isotretinoin