Pharmacokinetics and pharmacodynamics of testosterone enanthate and dihydrotestosterone enanthate in non-human primates

1990 ◽  
Vol 122 (4) ◽  
pp. 432-442 ◽  
Author(s):  
Gerhard F. Weinbauer ◽  
Bettina Jackwerth ◽  
Yong-Dal Yoon ◽  
Hermann M. Behre ◽  
Ching-Hei Yeung ◽  
...  
Keyword(s):  
Gnrh Agonist ◽  
Half Life ◽  
Rhesus Monkeys ◽  
Serum Testosterone ◽  
Testosterone Enanthate ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Elimination Phase ◽  
Cynomolgus Monkeys ◽  
Ejaculate Size ◽  
Testicular Size

Abstract. The pharmacokinetics and pharmacodynamics of testosterone enanthate and dihydrotestosteroneenanthate were compared in orchidectomized cynomolgus monkeys (Macaca fascicularis) and in intact GnRH agonist-suppressed rhesus monkeys (Macaca mulatta). Following a single im injection of 32.8 mg testosterone enanthate or 32.7 mg dihydrotestosteroneenanthate, i.e. 23.6 mg of pure steroid, in the orchidectomized cynomolgus monkeys, serum testosterone and dihydrotestosterone levels rose to 400 and 800% of baseline, respectively, within 24 h. Androgen levels remained in that range for 3-5 days followed by a continuous decline until baseline values were attained after 4-5 weeks. The areas under the testosterone- and dihydrotestosterone-curves did not differ significantly 2290±340 (dihydrotestosterone-enanthate) vs 2920±485 (testosteroneenanthate) suggesting that similar amounts of steroid had been released from the respective ester preparation. Mean half-life estimates of the terminal elimination phase were 4 and 7 days for testosterone-enanthate and dihydrotestosterone-enanthate, respectively. In a second experiment rhesus monkeys received, at 4-weekly intervals, sc implantation of a biodegradable polylactic:polyglycolide rod loaded with the GnRH agonist buserelin. The last injection was given during week 20. GnRH agonist treatment suppressed serum bioactive LH, testosterone and dihydrotestosterone levels, testicular size, sperm production, and seminal carnitine content. The ejaculatory response to electrostimulation and the masturbatory behaviour were abolished. Testosterone or dihydrotestosterone injections at the same doses as above were given in week 10, 14, 17 and 20 of GnRH agonist treatment. Serum testosterone and dihydrotestosterone levels were stimulated 9- and 4-fold, respectively. Mean half-life estimates for testosterone-enanthate and dihydrotestosterone were 5 and 7 days, respectively. Both ester preparations completely restored the ejaculatory response, ejaculate size, masturbatory behaviour, and seminal carnitine levels. In conclusion, androgen substitution with dihydrotestosterone-enanthate, in equivalent doses, is as effective as testosterone-enanthate in restoring reproductive functions in hypogonadal monkeys.

Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate

1995 ◽  
Vol 132 (4) ◽  
pp. 514-519 ◽  
Author(s):  
Carl-Joachim Partsch ◽  
Gerhard F Weinbauer ◽  
Ruiying Fang ◽  
Eberhard Nieschlag
Keyword(s):  
Body Weight ◽  
Serum Testosterone ◽  
Pharmacokinetic Analysis ◽  
Male Hypogonadism ◽  
Androgen Deficiency ◽  
Testosterone Enanthate ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Testosterone Undecanoate ◽  
Testosterone Levels

Partsch C-J, Weinbauer GF, Fang R, Nieschlag E. Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate. Eur J Endocrinol 1995;132:514–19. ISSN 0804–4643 Testosterone preparations producing constant physiological testosterone serum levels are desirable for long-term treatment of androgen deficiency. However, all injectable testosterone esters used clinically for substitution of male hypogonadism are characterized by unfavourable pharmacokinetics. We therefore tested two groups of five long-term orchidectomized cynomolgus monkeys (Macaca fascicularis), which received a single intramuscular injection of 10 mg/kg body weight of an injectable testosterone undecanoate (TU) preparation or testosterone enanthate (TE) in a preclinical study to assess the pharmacokinetic and pharmacodynamic characteristics of TU in comparison to TE. The dose was equivalent to 6.3 and 7.2 mg of pure testosterone per kilogram body weight in the TU and TE group, respectively. Following injection of TU, mean serum testosterone rose to 58 ± 18 nmol/l on day 1 and remained at moderately supraphysiological levels of 40–68 nmol/l for 45 days. Thereafter, testosterone levels were maintained in the normal range of intact monkeys for another 56 days. The TE injection resulted in highly supraphysiological levels of 100–177 nmol/l from immediately after the injection to day 5. A rapid decline followed and testosterone levels reached the lower limit of normal after 31 days. Serum testosterone levels were significantly higher in the TEthan in the TU-treated animals on days 0.5–7 (p < 0.05). Significantly lower testosterone levels were seen in the TE than in the TU group on days 16, 22, 25 and 31 (p < 0.05). Pharmacokinetic analysis of serum testosterone levels showed a significantly higher area under the curve for TU (4051 ± 939 vs 1771 ±208 nmol·h/l; p < 0.045), a longer residence time (40.7 ±4.1 vs 11.6 ±1.1 days; p <0.00012), a longer terminal half-life (25.7 ± 4.0 vs 10.3 ± 1.1 days; p < 0.0069), and a lower maximal testosterone concentration (73 ± 12 vs 177 ± 21 nmol/l; p < 0.0027). Following TU injection, oestradiol levels increased from 48 ± 8 pmol.l to a plateau of 80–118 pmol/l from day 1 to day 59. In contrast, TE injection resulted in a rapid increase of oestradiol levels to a maximum of 166 ± 29 pmol/l after 4 days (p < 0.05 vs TU- treated group). In the TU and TE groups levels below 80 pmol/l were reached after 66 and 16 days, respectively. Ejaculatory response was induced for 14 weeks in the TU animals in contrast to 7 weeks in the TE animals. Ejaculate weight reached a maximum of 533 ± 163 mg at day 52 in the TU group (p < 0.05 vs TE group). In the TE animals, the maximal ejaculate weight of 41 ± 17 mg was seen at day 16. Thus, with respect to androgen substitution therapy, TU showed pharmacokinetic and pharmacodynamic properties clearly superior to those of TE and may provide an important improvement in the substitution of male androgen deficiency and also for male contraception. E Nieschlag, Institute of Reproductive Medicine of the University, Steinfurter Str. 107, D-48149 Münster, Germany

Influence of N-methyl-d-aspartate on the reproductive axis of male Syrian hamsters

1993 ◽  
Vol 137 (2) ◽  
pp. 247-NP ◽  
Author(s):  
H. F. Urbanski ◽  
M. M. Fahy ◽  
P. M. Collins
Keyword(s):  
Hormone Secretion ◽  
Serum Testosterone ◽  
Inhibitory Effect ◽  
Stimulatory Action ◽  
Syrian Hamsters ◽  
Reproductive Axis ◽  
Treatment Paradigm ◽  
Testicular Size ◽  
Lh Releasing Hormone

ABSTRACT The influence of excitatory amino acids (EAAs) on reproductive neuroendocrine function was investigated in adult male Syrian hamsters of the LSH/Ss Lak strain. Before the study, the animals were maintained in a sexually regressed condition, under short days (SD) and subsequently were either transferred to long days (LD) or kept under SD, for a further 4 weeks. In the former group, photostimulation produced a predictable elevation in the hypophysial contents and serum concentrations of FSH and LH. This was accompanied by an increase in testicular size, an elevation in serum testosterone levels and an increase in spermatogenic activity; the SD hamsters remained sexually quiescent throughout the study. In contrast, SD hamsters that were given daily injections of the EAA agonist, N-methyl-d,l-aspartate (NMA: 50 mg/kg body weight, s.c.), showed stimulatory responses that were generally even more pronounced than those shown by the LD group. Surprisingly, an identical NMA treatment paradigm failed to cause a similar activation of the reproductive axis in LD hamsters that were given daily afternoon injections of melatonin (25 μg, s.c), even though the inhibitory effect of this melatonin treatment is generally regarded as being comparable with that produced by exposure to SD. Although EAAs can acutely stimulate the neurocircuitry that controls LH-releasing hormone secretion, the present findings suggest that EAAs might also exert a long-term stimulatory action by acting further upstream in the photoneuroendocrine pathway. Journal of Endocrinology (1993) 137, 247–252

Pituitary response to LRH and TRH stimulation and peripheral steroid hormones in conscious and anaesthetized adult male rhesus monkeys (Macaca mulatta)

1980 ◽  
Vol 93 (3) ◽  
pp. 287-293 ◽  
Author(s):  
E. Jean Wickings ◽  
E. Nieschlag
Keyword(s):  
Adult Male ◽  
Rhesus Monkeys ◽  
Serum Testosterone ◽  
Fold Increase ◽  
Serum Cortisol ◽  
Serum Levels ◽  
Biologically Active ◽  
Similar Response ◽  
Response Curves ◽  
Male Rhesus

Abstract. Adult male rhesus monkeys are aggressive animals and very difficult to handle. Hence experimental manipulations necessarily involve the use of restraint procedures, either chemical or physical, which may influence endocrine functions. Therefore, the effects of ketamine anaesthesia on basal hormone levels and on the pituitary response to LRH and TRH were investigated in 4 adult male rhesus monkeys. Values were compared to those obtained from the same animals restrained in primate chairs for approximately 48 h, a procedure to which they had been accustomed to over the preceding 6 months. Serum cortisol levels under anaesthesia were at all times lower than in conscious monkeys, but increased after 2 h to values twice as high as measured initially. Serum testosterone concentrations were not significantly different on the two occasions, but levels under anaesthesia were slightly higher initially than in the conscious monkeys, and decreased gradually over the 3 h test period. Initial prolactin levels were lower in the anaesthetized monkeys, and increased 2–3-fold after 90 min; values at 3 h were not significantly different from those in conscious monkeys. Intravenous TRH elicited a similar response in prolactin on both occasions, maximum values occurring after 15–30 min and returning to basal levels after 3 h. The maximum values attained and the area under the response curves were higher under anaesthesia. LRH stimulation resulted in a 15- and 30-fold increase in serum levels of biologically active LH, with and without anaesthesia, respectively. Basal levels were not significantly different on the two occasions. The area under the LH response curve was higher in 3 of the 4 monkeys without anaesthesia. The extent to which results in conscious monkeys are affected by stress is difficult to assess. Since neither handling technique allows for the collection of 'true' basal data, it is paramount to standardize and define the conditions under which experiments, and even routine blood sampling, are performed in male rhesus monkeys.

scholarly journals Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice

PLoS ONE ◽  
2014 ◽  
Vol 9 (1) ◽  
pp. e84877 ◽  
Author(s):  
Theofilos Poutahidis ◽  
Alex Springer ◽  
Tatiana Levkovich ◽  
Peimin Qi ◽  
Bernard J. Varian ◽  
...  
Keyword(s):  
Serum Testosterone ◽  
Testosterone Levels ◽  
Testicular Size ◽  
Probiotic Microbes

Follicle-stimulating hormone stimulates inhibin in the serum of male monkeys (Macaca mulatta)

1990 ◽  
Vol 122 (1) ◽  
pp. 96-100 ◽  
Author(s):  
Ulrich Fingscheidt ◽  
Gerhard F. Weinbauer ◽  
Shafiq A. Khan ◽  
Eberhard Nieschlag
Keyword(s):  
Macaca Mulatta ◽  
Half Life ◽  
Rhesus Monkeys ◽  
Follicle Stimulating Hormone ◽  
Serum Levels ◽  
Lag Time ◽  
Dependent Manner ◽  
Control Serum ◽  
Dose Dependent ◽  
Stimulating Hormone

Abstract. Three adult rhesus monkeys were injected intramuscularly with human FSH at doses of 2, 10 or 25 IU/kg in a cross-over design with 3-week intervals between injections. On each occasion a fourth animal received saline only as control. Serum levels of exogenous FSH were monitored by a fluoroimmunoassay specific for human FSH. Serum inhibin was measured by a heterologous radioimmunoassay. Each FSH injection was followed by a rise in serum inhibin in a dose-dependent manner. The half-life of human FSH in rhesus monkeys ranged from 25.1 to 32.9 h with no significant differences between doses. The rise of inhibin occurred with a lag time of 53.3 to 61.9 h after injection of FSH, independent of the dose administered. These findings support the concept that inhibin secretion in male primates is stimulated by FSH.

Pharmacokinetics and Pharmacodynamics of Pegylated Interferon Lambda-1 in Cynomolgus Monkeys

2012 ◽  
Vol 32 (5) ◽  
pp. 198-206 ◽  
Author(s):  
Kelly A. Byrnes-Blake ◽  
Susan Pederson ◽  
Kevin M. Klucher ◽  
Monica Anderson-Haley ◽  
Dennis M. Miller ◽  
...  
Keyword(s):  
Pegylated Interferon ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Cynomolgus Monkeys ◽  
Interferon Lambda

Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys

1991 ◽  
Vol 260 (4) ◽  
pp. R804-R810 ◽  
Author(s):  
T. Lenz ◽  
J. E. Sealey ◽  
T. Maack ◽  
G. D. James ◽  
R. L. Heinrikson ◽  
...  
Keyword(s):  
Half Life ◽  
Renal Plasma Flow ◽  
Plasma Renin ◽  
Apparent Volume ◽  
Reproductive Organs ◽  
Volume Of Distribution ◽  
Plasma Testosterone ◽  
Metabolic Clearance ◽  
Cynomolgus Monkeys ◽  
Pharmacokinetic Properties

Prorenin is found in human plasma, kidneys, and reproductive organs. We investigated the physiological and pharmacokinetic properties of plasma prorenin, and its plasma conversion to active renin, by bolus infusions of human recombinant prorenin (0.5, 2, 20 micrograms; n = 4/dose) into anesthetized male cynomolgus monkeys. The infused prorenin had 3% intrinsic renin activity. Plasma prorenin rose from 61 +/- 6 to 101 +/- 11, 570 +/- 46, and 7,700 +/- 390 ng.ml-1.h-1, respectively, after 5 min. Plasma renin increased to 3% of total renin, angiotensin II increased less than twofold, and aldosterone did not change. Plasma testosterone fell slightly (P less than 0.01). Mean arterial pressure (MAP) fell slowly from 104 +/- 3 to 93 +/- 3 mmHg at 60 min (P less than 0.001). Heart rate, glomerular filtration rate, renal plasma flow, and urinary sodium and potassium excretion were unchanged. For the 2- and 20-micrograms doses, respectively, effective half-life of plasma decay was 47 +/- 4.9 and 109 +/- 21 min (P less than 0.05), apparent volume of distribution was 145 +/- 11 and 166 +/- 35 ml/kg, and metabolic clearance rate was 2.30 +/- 0.44 and 1.08 +/- 0.14 ml.min-1.kg-1 (P less than 0.01). In conclusion, neither the hormonal nor the physiological response to infusion of pharmacologic levels of recombinant human prorenin into monkeys provide evidence for conversion of circulating prorenin to renin. MAP did not increase and actually fell without commensurate effects on renal function. The half-life of recombinant prorenin was similar to that of renin.

scholarly journals Pharmacokinetics of L-749,345, a long-acting carbapenem antibiotic, in primates.

1997 ◽  
Vol 41 (8) ◽  
pp. 1743-1748 ◽  
Author(s):  
J G Sundelof ◽  
R Hajdu ◽  
C J Gill ◽  
R Thompson ◽  
H Rosen ◽  
...  
Keyword(s):  
Half Life ◽  
Single Agent ◽  
Bioactive Metabolites ◽  
Urinary Recovery ◽  
Elimination Phase ◽  
Phase Ii Clinical Trials ◽  
Improved Stability ◽  
Time Courses ◽  
Long Acting ◽  
Carbapenem Antibiotic

L-749,345 is a carbapenem antibiotic, currently in phase II clinical trials, which possesses a broad antibacterial spectrum and extended half-life. The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpanzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM and approached CTX in its ability to persist in the circulation. Levels of binding to protein, in the range of clinically relevant concentrations in serum, are virtually equivalent for L-749,345 and CTX in humans. Results of a crossover bioassay versus those of a high-pressure liquid chromatography assay of 1-g human samples showed that there were no bioactive metabolites of L-749,345. The extended half-life at elimination phase of L-749,345 allows consideration of single daily dosing. In contrast to results with IPM, the improved stability of L-749,345 with respect to hydrolysis by the renal dehydropeptidase I (0.25 times the rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.

Pharmacokinetics, Pharmacodynamics and Tolerability of a Potent, Non-peptidic, GP IIb/IIIa Receptor Antagonist following Multiple Oral Administrations of a Prodrug Form

1998 ◽  
Vol 79 (01) ◽  
pp. 169-176 ◽  
Author(s):  
Nishit Modi ◽  
Sherron Bullens ◽  
Cheryl Pater ◽  
Michael Lipari ◽  
Kirk Robarge ◽  
...  
Keyword(s):  
Half Life ◽  
Rhesus Monkeys ◽  
Ex Vivo ◽  
Active Form ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
A Value ◽  
Terminal Half Life ◽  
The Right

SummaryRo 44-3888 is a potent and selective antagonist of GP IIb/IIIa. Following IV administration to rhesus monkeys, the (mean ± SD.) clear ance, volume of distribution and terminal half-life of Ro 44-3888 were 4.4 ± 1.8 ml/min/kg, 0.8 ± 0.4 l/kg and 2.5 ± 0.8 h respectively. Oral administration of Ro 48-3657 (1 mg/kg), a doubly protected prodrug form, produced peak concentrations of Ro 44-3888 (152 ± 51 ng/ml), 4.2 ± 2.2 h after dosing. Terminal half-life and estimated bioavailabil ity were 5.1 ± 1.6 h and 33 ± 6% respectively. No effect on blood pressure, heart rate or platelet counts were seen. Adenosine diphosohate (ADP) induced platelet aggregation (PA) and cutaneous bleeding times (CBT) were determined prior to and after the last of 8 daily oral administrations of Ro 48-3657 (0.25 or 0.5 mg/kg) to eight rhesus monkeys. Peak and trough plasma concentrations were proportional to dose and steady state was achieved after the second administration. Inhibition of PA and prolongation of CBT were concentration dependent. The ex vivo IC50 (82 nM) for ADP-mediated PA correlated with a value (58 nM) determined in vitro. The CBT response curve was displaced to the right of the PA curve. CBT was prolonged to ≥25 min when levels of Ro 44-3888 exceeded 190 nM and PA was >90% inhibited. Therefore, in rhesus monkeys, Ro 48-3657 is reproducibly absorbed and converted to its active form, is well tolerated, and has a concentration-dependent effect on PA and CBT. These properties make Ro 48-3657 an attractive candidate for evaluation in patients at high risk for arterial thrombosis.

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