Accumulation of norethindrone and individual metabolites in human plasma during short- and long-term administration of a contraceptive dosage.

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.