Doping in sport: 3. Metabolic conversion of oral norethisterone to urinary 19-norandrosterone.
The detection of 19 norandrosterone (19-NA) in a competitor's urine sample is taken as prima facie evidence of administration of nandrolone or other 19-norsteroid but a potential problem is that administration of norethisterone, a progestogen used for menstrual disorders and for hormonal contraception, also results in the excretion of 19-NA that can exceed the laboratory reporting threshold of 2ng/mL. The contribution of norethisterone to urinary 19-NA with and without 19-norandrostenedione, a known norethisterone tablet impurity, requires evaluation. Preparations containing, either <2ng or 1microg 19-norandrostenedione impurity per 5mg of norethisterone, administered to female volunteers (n=10) in doses comparable to those used for menstrual disorders (5mg three times daily for 10 days), resulted in maximal 19-NA concentrations of 51 and 63ng/mL, respectively. The maximal concentration of 19-NA, 2h post-administration of a single 1microg dose of 19-norandrostenedione, was 2.4ng/mL. These results prove unequivocally that norethisterone is metabolized to 19-NA and that there is only a minor contribution from the impurity 19-norandrostenedione. Administration to women (n=30) of a single contraceptive tablet containing norethisterone (1mg) with one of the highest proportions of the impurity 19-norandrostenedione ( approximately 0.5microg, 0.05%, w/w) resulted in a urinary 19-NA concentration of 9.1ng/mL, with a maximum concentration ratio of 19-NA to the norethisterone metabolite 3alpha,5beta-tetrahydronorethisterone of 0.36. We provide data that should remove the need for time-consuming follow-up investigations to consider whether doping with 19-norandrogens has occurred.
Walker
Christopher J
CJ
King's College London, Drug Control Centre, Pharmaceutical Science Research Division, Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, United Kingdom.
Cowan
David A
DA
James
Vivian H T
VH
Lau
Joanne C Y
JC
Kicman
Andrew T
AT
D000284:Administration, Oral; D000328:Adult; D002853:Chromatography, Liquid; D004300:Doping in Sports; D004962:Estranes / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D015394:Molecular Structure; D009640:Norethindrone / Q000378:metabolism* / Q000652:urine*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D004962:Estranes; C036015:19-norandrosterone; D009640:Norethindrone