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Data from toxicokinetic assessment published within the scope of NTP (NIH, US) assessment [NTP Technical Report 560, NIH Publication No. 10-5901, September 2010]:
Androstenedione was readily absorbed following oral administration to rodents. The bioavailability of the oral doses of androstenedione in rats was low due to extensive metabolism. Approximately 80 to 90% of single oral doses of 1, 10, or 100 mg/kg was excreted in urine of rats and mice within 72 hours. The half-lives of the 14C in rat plasma ranged from 4.4 to 7.1 hours. The absorption, distribution, metabolism, and excretion of exogenous androstenedione in humans are not well characterized and are complicated by androstenedione transformation in various tissues to other hormones.

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Additional information

The Absorption, Distribution, Metabolism, and Excretion of Androstendione was discussed within the scope of a NTP Technical Report:

[NTP Technical Report 560, NIH Publication No. 10-5901, September 2010]

Experimental Animals

"Androstenedione can be metabolized to more potent hormones, which are known carcinogens, testosterone or estrone and ultimately to estradiol by the enzymes 17beta hydroxysteroid dehydrogenase (17beta-HSD) and aromatase (CYP19). Endogenous androstenedione production through the steroidogenic pathway involves multiple enzymes, including CYP17, an enzyme with hydroxylase and lyase activities. In the rat, CYP17 preferentially catalyzes the formation of androstenedione from progesterone in the delta 4 biosynthetic pathway, whereas in humans, androstenedione arises preferentially from CYP17 catalyzation of dehydroepiandrosterone (DHEA) from pregnenolone in the delta 5 pathway (Brock and Waterman, Biochemistry 38, 1999, 1598 -1606). Androstenedione undergoes extensive metabolism in humans and animals, including hydroxylation, reduction, and conjugation to glucuronic acid or sulfate.

The metabolism and disposition of 14C-labeled androstenedione were investigated in male and female F344/N rats, B6C3F1 mice, and beagle dogs in studies sponsored by the NTP (Green and Catz, NIEHS Contract No. N01-ES-95437, SRI International, Menlo Park, CA, 2007). Androstenedione was readily absorbed following oral administration to rodents. Approximately 80 to 90% of single oral doses of 1, 10, or 100 mg/kg (in 0.5% methylcellulose) was excreted in urine of rats and mice within 72 hours. The remaining dose (in all treatment groups) was mostly excreted in feces, with less than 1% remaining in tissues after 72 hours. The bioavailability of the oral doses of androstenedione in rats was low due to extensive metabolism. Several unidentified metabolites,but not androstenedione, were detected in rat plasma samples collected from 0.5 to 24 hours after dosing. The half-lives of the 14C in rat plasma ranged from 4.4 to 7.1 hours among the three doses, and were highest in the female treatment groups. No 14C-derived androstenedione, estradiol, estrone, or testosterone was detected in the urine of these animals. Although the metabolic profile of the 14C in urine differed significantly between male and female rats, the metabolites were poorly resolved and were not identified. Metabolism of androstenedione was not characterized in vivo in the mouse. Dogs excreted most, if not all, of an oral dose of either 1 or 100 mg/kg within 120 hours of dosing; however, in contrast to rodents, the 14C was equally excreted in urine and feces.

In the Green and Catz studies (NIEHS Contract No. N01-ES-95437, SRI International, Menlo Park, CA, 2007), the half-lives of the 14C in plasma were similar between male and female rats (approximately 6 hours) following intravenous (IV) administration, were higher following oral administration than IV administration, and were higher in females than in males (16 to 17 hours for females versus 11 hours for males) following dermal administration. Three minutes after IV administration, the 14C in rat plasma consisted primarily of androstenedione (80%). Testosterone, 6beta-hydroxyandrostenedione, epiandrosterone, and 5alpha-androstenedione were also identified in plasma by co-elution with authentic standards. Other unidentified metabolites were present at later timepoints. In dogs, the half-lives of the parent chemical after 1 mg/kg IV administration were 0.9 hours for males and 0.4 hours for females. In dogs receiving 100 mg/kg androstenedione by oral administration, the compound was detected in plasma samples and the half-lives were 0.4 and 0.2 hours for males and females, respectively. As in rats, plasma and urine of orally treated dogs contained many poorly resolved metabolites that were not identified. No 14C estrone or estradiol was detected in plasma or urine and no 14C androstenedione or testosterone was detected in urine after IV or oral administration. Differences in the 14C metabolic profile in urine of male and female dogs were minor.

The metabolism of androstenedione was further investigated in hepatocytes of male and female F344/N rats, B6C3F1 mice, and beagle dogs in the Green and Catz (NIEHS Contract No. N01-ES-95437, SRI International, Menlo Park, CA, 2007) studies. The rate of androstenedione metabolism was highest in the rat and lowest in the dog. There was a clear sex difference in androstenedione metabolism in rat hepatocytes. Mass spectrometry indicated that the major metabolite formed by male rat hepatocytes incubated with 100¿M androstenedione for 4 hours was 16alpha-hydroxyandrostenedione. Other identified metabolites were 6beta-hydroxyandrostenedione, 16alpha-hydroxyandrosterone, epiandrosterone, and androsterone glucuronide. Female rat hepatocytes metabolized androstenedione predominantly via a 5alpha-reduced pathway as indicated by the formation of two major metabolites, 5alpha-androstenedione and androsterone, in the 4 hour incubation. Metabolites detected in female hepatocytes 24 hours after incubation of 100¿M androstenedione included 5alpha-dihydrotestosterone glucuronide, 5alpha-androstenediol glucuronide, androsterone glucuronide, epiandrosterone sulfate, and androsterone sulfate. In contrast to rats, the metabolic profiles were similar in male and female mouse liver cells. The primary pathway of androstenedione metabolism in mouse hepatocytes appeared to be conversion to testosterone followed by glucuronidation, resulting in the formation of the major metabolite, testosterone glucuronide. Female mouse hepatocytes metabolized androstenedione at a faster rate, but had metabolites common to both sexes: testosterone, 5alpha-dihydrotestosterone glucuronide, and 6beta-hydroxyandrostenedione. Approximately 50% of 100¿M androstenedione was unmetabolized at 4 hours by male and female dog hepatocytes. Metabolites common to males and females at 4 hours were testosterone glucuronide, androsterone glucuronide, 6alpha-hydroxyandrostenedione, 6beta-hydroxyandrostenedione, and 16alpha-hydroxyandrostenedione."

Humans

"The absorption, distribution, metabolism, and excretion of exogenous androstenedione in humans are not well characterized and are complicated by androstenedione transformation in various tissues to other hormones. Androstenedione has a half-life of 30 minutes in pregnant and nonpregnant women (Belisle et al., Am. J. Obstet. Gynecol. 136, 1980, 1030-1035). Circulating levels and excretion rates of several hormones increase after androstenedione dosing. Administration of 100 to 300 mg androstenedione/day for up to 28 days to men increased serum concentrations of androstenedione, testosterone, dihydrotestosterone, estradiol, and increased excretion of testosterone glucuronide, dihydrotestosterone, etiocholanolone, and androsterone (Leder et al., J. Clin. Endocrinol. Metab. 86, 2001, 3654-3658 and J. Clin. Endocrinol. Metab. 87, 2002, 5449 -5454; Brown et al., J. Clin. Endocr. Metab. 89, 2004, 6235-6238). The increase in circulating testosterone after androstenedione exposure is not a consistent effect and may be related to androstenedione dose, exposure length, and age of the individual. Testosterone was not elevated after a 28-day exposure to 200 mg androstenedione/day or 8 weeks of exposure to 300 mg androstenedione/day (King et al., JAMA 281, 1999, 2020-2028; Beckham and Earnest, Br. J. Sports Med. 37, 2003, 212-218). Prolonged androstenedione exposure (200 mg/day for 12 weeks) elevated androstenedione, estradiol, and estrone serum concentrations, but not serum testosterone concentrations, which may be due to a negative endocrine feedback loop (Broeder et al., 2000). However, a large dose (1,500 mg/day) of androstenedione given to hypogonadal men increased circulating levels of androstenedione and testosterone after a 12-week exposure (Jasuja et al., J. Clin. Endrocinol. Metab. 90, 2005, 855-863). Serum androstenedione and testosterone concentrations rise considerably in women compared to men after administration, likely due to the low concentrations of androgens normally circulating in women (Brown et al., Horm. Metab. Res. 36, 2004, 62-66.). Androstenedione metabolism in human hepatocytes consists of hydroxylation and reduction resulting in multiple metabolites that may remain free or conjugated to glucuronide or sulfate (Lévesque et al., J. Chromatogr. B. Analyt. Technol. Biomed. Life Sci. 780, 2002, 145-153). In the human hepatocyte studies conducted by the NTP (Green and Catz, NIEHS Contract No. N01-ES-95437, SRI International, Menlo Park, CA, 2007), androstenedione metabolism in male and female donors was generally similar with 5alpha-reduction and conjugation forming the two major metabolites androsterone glucuronide and epiandrosterone sulfate. In these studies, testosterone was a minor metabolite in male and female cultures, and mono-hydroxylated metabolites of androstenedione and testosterone were highest in the young male donor (20 years old)."