Testosterone

Endpoint summary

Description of key information

Testosterone is absorbed rapidly following oral administration and undergoes extensive first pass metabolism. Absorption and metabolism of the lipid soluble esters of testosterone is slower than that of the parent molecule.

Additional information

For testosterone, only limited data were available. Further data were found for testosterone propionate and other esters of testosterone. Although toxicokinetic data are not required to fulfil the Annex VII obligations for a 1 -10 tpa registration dossier, summary data from the open literature are included here as supporting data. Read-across justification summary is attached to this endpoint summary.

Toxicokinetics

 

Effect	Literature
The absorption after oral dosing is rapid for testosterone, but there is extensive first-pass hepatic metabolism Absorption from subcutaneous or intramuscular depots is slow for the lipid-soluble esters such as the cypionate or enanthate, and for oily suspensions.	International Programme on Chemical Safety, Poisons Information Monograph 519, Testosterone, March 1998.
Testosterone esters, prepared for parenter al administration are less polar than the free steroids. They are absorbed more slowly being effective if given with 1 to 3 weeks intervals. Some preparations are effective even when given at 12 week intervals	Wilson J D., 1992. Androgens. In: Goodman Gilman A., Rall T W, Nies A S, & Taylor P. (eds) Goodman and Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill,as cited by International Programme on Chemical Safety, Poisons Information Monograph 519, Testosterone, March 1998.

Distribution

 

Effect	Literature
Testosterone is highly protein bound (98%) to a specific protein called sex-hormone binding globulin. In tissues, it is transformed by steroid 5-alphareductase to dihydrotestosterone, the more active compound.	Prod. Info., 1994 as cited by International Programme on Chemical Safety, Poisons Information Monograph 519, Testosterone, March 1998.
Using a novel combination of a continuum-solvent model and the downhill simplex search method for the calculation of the free energy of interaction of steroid hormones including testosterone with lipid membranes, calculations imply that the hormones may rapidly cross biomembrane barriers and distribute freely in the body.	Free Diffusion of Steroid Hormones Across Biomembranes: A Simplex Search with Implicit Solvent Model Calculations.Idit Oren, Sarel J. Fleishman, Amit Kessel, and Nir Ben-Tal. Biophysical Journal Volume 87 August 2004 768–779

Metabolism - Animal Data

 

Test system	Substance	Application	Effect	Citation
			The metabolism of absorbed drug is rapid, and the elimination half-life from plasma is very short. The duration of the biological effects is therefore determined almost entirely by the rate of absorption from subcutaneous or intramuscular depots with previous de-esterification.	Wilson J D., 1992. Androgens. In: Goodman Gilman A., Rall T W, Nies A S, & Taylor P. (eds) Goodman and Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill,as cited by International Programme on Chemical Safety, Poisons Information Monograph 519, Testosterone, March 1998.
Rat, male	Testosterone (labelled)	Gavage	About ¼ appears as biliary metabolites within 12 h as glucuronides and sulphates (1:1), major metabolic routes are reductive and lead to 5α-dihydrotestosterone, androsterone and isomers there of (epiandrosterone, 3α-hydroxy-5β-androstan-17-one) and androstandiols (5α-androstan-3α, 17β-diol, 5β-androstan-3α, 17β-diol, 5α-androstan-3b,17β-diol.	Hetzel et al., 1974 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rat			Hydroxylations at position 7α, 11β, 15α and 15β	Matsui&Kinuyama, 1977 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rat (both sexes)			Quantitative differences between sexes due to androgen or oestrogen dependency of metabolic enzymes	Matsui et al, 1974 and 1978, Ghraf et al. 1975 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Macaca mulatta			Metabolism similar to baboon and human, but rate of excretion more baboon-like	Yamamoto et al., 1978 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
RAT Liver Prostate and seminal vesicles and uterus			Positive for metabolizing testosterone	Hoffmann et al., 1975 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rat Small intestine			Positive for metabolizing testosterone	Geelen, 1977 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rabbit Placenta			Positive for metabolizing testosterone	Marchut, 1977 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rodent Testis			Positive for metabolizing testosterone	Mizutani et al. 1977 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Primate Brain			Positive for metabolizing testosterone	Sholiton et al., 1974 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Rat	Testosterone undecanoate in oily solution	Oral	Conversion to the parent compound in the intestinal wall	Coert at al. 1975, IARC as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
			There is little clinical interest in oral forms of testosterone (i.e. fine-particle formulations), as the high doses required to overcome first-pass metabolism in the liver result in a high hepatic load.	WHO (1992) Guidelines for the Use of Androgens in Men (WHO/HPR/MALE/92), Geneva, Special Programme of Research, Development and Research Training in Human Reproduction.
Rodent	testosterone		Significant differences are found between the metabolic pathways of testosterone in rodents and humans. Sex-specific regulation of cytochrome P450s has not been found in human liver, although sex differences in the metabolism of xenobiotics exist	Kedderis, G.L. & Mugford, C.A. (1998) Sex-dependent metabolism of xenobiotics. CIIT Activities, 18, 1-7. In:Toxicological Evaluation Of Certain Veterinary Drug Residues. In Food Who Food Additives Series: 43 Prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) World Health Organization, Geneva, 2000 IPCS - International Programme on Chemical Safety

Metabolism - Human Data

 

Test system	Substance	Application	Effect	Literature
Human	Testosterone	Injection	Main urinary metabolites are 17-ketosteroids (androsterone and isomers) and partially estrogens	Kochakin&Arimasa, 1976 as cited by IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work), V21 (1979)
Human	testosterone undecanoate	oral administration of 25 mg testosterone or 40 mg testosterone undecanoate (approximately 25 mg testosterone) to young women, and were compared with that in subjects receiving testosterone at 1.5 μg/kg bw by intravenous administration	Bioavailable testosterone represented 3.6% of administered testosterone and 6.8% of administered testosterone undecanoate. The low bioavailability of orally administered testosterone has been attributed to its high metabolic clearance rate, 25 ml/min per kg. The estimated bioavailability provides justification for the high dose (120-140 mg/day) considered to be necessary to replace daily production (5-7 mg)	Tauber, U., Schroder, K., Dusterberg, B. & Matthes, H. (1986) Absolute bioavailability of testosterone after oral administration of testosterone-undecanoate and testosterone. Eur. J. Drug Metab. Pharmacokinet., 11, 145-149. In: Toxicological Evaluation Of Certain Veterinary Drug Residues. In Food Who Food Additives Series: 43 Prepared by the Fifty-second meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA) World Health Organization, Geneva, 2000 IPCS - International Programme on Chemical Safety

Elimination

Test system	Substance	Application	Effect	Literature
Rat	Testosterone (radiolabelled)		About 90% of the radioactivity appears in the urine as glucuronic or sulfate conjugates, and 6% of the unconjugated testosterone in the faeces; there is some enterohepatic recirculation. Small amounts of androstenediol and estrogens are excreted in the urine.	Wilson J D., 1992. Androgens. In: Goodman Gilman A., Rall T W, Nies A S, & Taylor P. (eds) Goodman and Gilman's Pharmacological Basis of Therapeutics. McGraw-Hill,as cited by International Programme on Chemical Safety, Poisons Information Monograph 519, Testosterone, March 1998.