Blood levels of free, sulfate, and glucuronide conjugates of norethindrone (NE) and its ring A reduced metabolites 17alpha-ethynyl-5beta-estrane-3alpha, 17beta-diol and 17alpha-ethynyl-5alpha-estrane-3alpha, 17beta-diol were measured in a female volunteer who received six consecutive daily doses of 2.5 mg. of NE and in four female volunteers undergoing chronic treatment with Orthonovum 2 mg. (2 mg. of NE and 0.1 mg. of mestranol [ME]). The blood levels were quantified by gas chromatograph-mass spectrometry. During treatment for 6 days with 2.5 mg. of NE daily, the 3 hour blood levels of NE and the ring A reduced metabolites increased in a stepwise fashion. During long-term treatment the concentrations of NE, NE sulfate, and the conjugates of the ring A reduced metabolites were seen to build up to a peak at approximately the midpoint of the treatment phase of each cycle, and drop to near baseline during the time when no drug was administered. Individuals varied as to their tendency to accumulate the drug and metabolites, and as to the relative proportion of metabolites formed.
PIP: The accumulation of norethindrone (NE) and its ring A reduced metabolites in human plasma during short- and long-term administration of the contraceptive Orthonovum (2 mg NE plus .1 mg mestranol) was investigated. Free, sulfate, and glucuronide conjugates of NA and 17 alpha-ethynyl-5 beta-estrane-3 alpha,17 beta-diol and 17 alpha-ethynyl-5 alpha-estrane-3 alpha,17 beta-diol were measured in a female volunteer who received 6 consecutive doses of 2.5 mg NE/day and in 4 female volunteers, aged 20-37 years, undergoing chronic treatment with Orthonovum. Gas chromatograph-mass spectrometry were used to measure the blood levels. During treatment for 6 days with 2.5 mg/day, the 3 hour blood levels of NE and the metabolites increased in a stepwise fashion. During long-term treatment, NE, NE sulfate, and the conjugates of the metabolites were built up to a peak about midpoint of the treatment phase of each cycle, and dropped to near baseline when no drug was administered. The individuals varied as to their tendency to accumulate the drug and metabolites, and the relative proportion of metabolites formed.