http://jpet.aspetjournals.org/cgi/content/full/281/1/93


Pharmacokinetics and Pharmacodynamics of Nandrolone Esters in Oil Vehicle: Effects of Ester, Injection Site and Injection Volume1
Charles F. Minto, Christopher Howe, Susan Wishart, Ann J. Conway and David J. Handelsman
Department of Anaesthesia and Pain Management, Royal North Shore Hospital (C.F.M.), and Andrology Unit, Royal Prince Alfred Hospital, Department of Medicine (C.H., S.W., A.J.C., D.J.H.), University of Sydney, Sydney, Australia


Abstract
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
We studied healthy men who underwent blood sampling for plasma nandrolone, testosterone and inhibin measurements before and for 32 days after a single i.m. injection of 100 mg of nandrolone ester in arachis oil. Twenty-three men were randomized into groups receiving nandrolone phenylpropionate (group 1, n = 7) or nandrolone decanoate (group 2, n = 6) injected into the gluteal muscle in 4 ml of arachis oil vehicle or nandrolone decanoate in 1 ml of arachis oil vehicle injected into either the gluteal (group 3, n = 5) or deltoid (group 4, n = 5) muscles. Plasma nandrolone, testosterone and inhibin concentrations were analyzed by a mixed-effects indirect response model. Plasma nandrolone concentrations were influenced (P < .001) by different esters and injection sites, with higher and earlier peaks with the phenylpropionate ester, compared with the decanoate ester. After nandrolone decanoate injection, the highest bioavailability and peak nandrolone levels were observed with the 1-ml gluteal injection. Plasma testosterone concentrations were also influenced (P < .001) by the ester and injection site, with the most rapid, but briefest, suppression being due to the phenylpropionate ester, whereas the most sustained suppression was achieved with the 1-ml gluteal injection. Plasma inhibin concentrations were also significantly influenced by injection volume and site, with the lowest nadir occurring after the nandrolone decanoate 1-ml gluteal injection. Thus, the bioavailability and physiological effects of a nandrolone ester in an oil vehicle are greatest when the ester is injected in a small (1 ml vs. 4 ml) volume and into the gluteal vs. deltoid muscle. We conclude that the side-chain ester and the injection site and volume influence the pharmacokinetics and pharmacodynamics of nandrolone esters in an oil vehicle in men.


Introduction
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
For decades, administration of androgens such as testosterone and 19-nor-testosterone has been most frequently via depot i.m. injections of steroid esters dissolved in a vegetable oil vehicle (Junkman, 1957; Behre et al., 1990). Such i.m. injections provide sustained androgen release into the circulation and have remained the mainstay of androgen replacement therapy for the last few decades (Nieschlag and Behre, 1990), although the basic pharmacological mechanisms are complex and only partially understood (Zuidema et al., 1988). The basic pharmacology of this depot androgen formulation differs among species (van der Vies, 1965) but has been little studied in humans. The current understanding is that the rate-limiting mechanism governing the appearance of active steroid in the bloodstream is the retention of steroid esters from the oil vehicle depot due to oil/water partitioning, with gradual release into the extracellular fluid, where esters are rapidly hydrolyzed to liberate biologically active steroid. Other physiological and physico-chemical factors that could influence steroid appearance in the bloodstream include the chemistry of the side-chain ester (hydrophobicity, steric hindrance of hydrolysis and solubility), injection factors (depth, site and volume, pH and osmolarity of the solution), exercise and systemic illness. The influence of site and volume of injection on the release kinetics of androgen esters from oil vehicle depots has, however, not been systematically investigated in humans.

This study compared the pharmacokinetics and pharmacodynamics of two currently available esters of nandrolone, the decanoate and phenylpropionate, as well as the influence of i.m. injection sites (gluteal vs. deltoid) and injection volumes (4 ml vs. 1 ml). In addition to measuring plasma nandrolone to investigate pharmacokinetics, we measured plasma testosterone and inhibin by radioimmunoassay to determine the pharmacodynamic effects of nandrolone-induced inhibition of pituitary gonadotrophin secretion, as reflected in LH-dependent Leydig (testosterone) and FSH-dependent Sertoli (inhibin) cell function in healthy men. We analyzed these data using an indirect pharmacodynamic response model, which has demonstrated, for the first time, prominent pharmacological differences between esters differing in only a single carbon in the side-chain, as well as systematic differences attributable to injection site and volume in humans.