A STUDY OF THE MECHANISM RESPONSIBLE FOR THE SENSITIVITY OF NEWBORN RATS TO PREGNANOLONE

¹ Department of Pediatrics and Lt. Joseph P. Kennedy, Jr. Laboratories for Molecular Medicine, Stanford University School of Medicine, Stanford, California

Studies in rats of the acute toxicity of pregnanolone, a pharmacologically active metabolite of progesterone and pregnanedione, revealed a marked increase in the lethal dose from birth to weaning. The mechanisms underlying the sensitivity of the newborn were: 1) decreased receptor threshold; 2) lesser hepatic biotransformation; and 3) increased permeability of the brain. Of these, the change in brain threshold, not decreased metabolism, was quantitatively most significant. A number of unknown metabolites in addition to pregnanediol were found in the liver. Conjugates were primarily in the form of sulfates, rather than glucuronides.