Fundamental understanding of drug absorption from a parenteral oil depot.

Oil depots are parenteral drug formulations meant for sustained release of lipophilic compounds. Until now, a comprehensive understanding of the mechanism of drug absorption from oil depots is lacking. The aim of this paper was to fill this gap. A clinical study with healthy volunteers was conducted. An oil depot with nandrolone decanoate and benzyl alcohol was subcutaneously administered in the upper arm of female volunteers. Pharmacokinetic profiles of both substances were related to each other and to literature data. Benzyl alcohol absorbs much more rapidly than nandrolone. In detail, it appears that benzyl alcohol enters the central compartment directly, while nandrolone decanoate is recovered in serum after a lag time. This lag time is also seen in literature data, although not reported explicitly. The absorption of nandrolone is enhanced by the presence of benzyl alcohol. This is most likely an effect of altered oil viscosity and partition coefficient between the oil and aqueous phase. The absorption rate constant of compounds is found to be related to the logP of the solubilized prodrug. The absorption rate is however not only determined by the physico-chemical properties of the formulation but also by the tissue properties. Here, it is argued that lymphatic flow must be considered as a relevant parameter.

Preclinical development of a neutral, estrogen receptor-targeted, tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative for imaging of breast and endometrial cancers.

UNLABELLED: Breast and endometrial cancers are the most common invasive malignancies in women, with more than 217,000 new diagnoses per year in the United States. These cancers are often classified into 2 subtypes based on the expression of the classical estrogen receptor. In this study, we describe a new structural class of neutral tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivatives for potential use in breast and endometrial cancer imaging. METHODS: The 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative was synthesized via the Sonogashira cross-coupling reaction and radiolabeled via the tricarbonyl approach. Radiochemical purity was assessed by high-performance liquid chromatography. Cell-binding studies were performed with human breast adenocarcinoma MCF-7 cells. The in vivo biodistribution of the 99mTc(I) derivative was evaluated in virgin female C57BL/6 mice in defined phases of the estrous cycle. Biodistribution and SPECT/CT studies were performed with mice bearing MCF-7 and primary human endometrial tumors. RESULTS: Radiochemical analysis demonstrated that the postpurification purity of the 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative was > or =95%, with a specific activity of 99mTc of 47.5 TBq/mmol. Cell-binding studies yielded a dissociation constant (mean +/- SEM) of 11 +/- 1.5 nM. In vivo studies revealed that receptor-mediated uptake was present in all phases of the estrous cycle in reproductive organs and mammary glands but was highest during the diestrous phase of the estrous cycle. Despite high nonspecific uptake in the liver, significant receptor-mediated uptake was observed in target tissues and estrogen receptor-expressing tumors (0.67% for MCF-7 tumors and 0.77% for endometrial tumors). Tumor uptake was reduced by approximately 50% on coinjection with 17beta-estradiol. CONCLUSION: We have characterized a novel neutral tridentate 99mTc(I)-estradiol-pyridin-2-yl hydrazine derivative for potential use in breast and endometrial cancer imaging. This study represents the first step on a path toward the design of estrogen-based Tc-labeled tracers with improved targeting and SPECT imaging characteristics.

Plasticity in anterior hypothalamic vasopressin correlates with aggression during anabolic-androgenic steroid withdrawal in hamsters.

In hamsters, adolescent anabolic-androgenic steroid (AAS) exposure facilitates offensive aggression, in part by altering the development and activity of anterior hypothalamic arginine vasopressin (AH-AVP). This study assessed whether these effects were lasting by examining aggression and AH-AVP during AAS withdrawal. Adolescent hamsters administered AAS were tested as adults for aggression at 1, 4, 11, 18, or 25 days of withdrawal, sacrificed the following day, and examined for AH-AVP afferent innervation using immunohistochemistry. Through Day 12 of withdrawal, aggression and AVP were significantly higher in AAS-treated hamsters than in controls. These differences were no longer observable by Day 19 of withdrawal, at which point the behavior and neurobiology of AAS-treated hamsters reverted to that observed in controls. These data indicate that adolescent AAS exposure has short-term, reversible effects on both aggression and AH-AVP, correlating AH-AVP with the aggressive/nonaggressive behavioral phenotype during AAS withdrawal.

Quantification and profiling of 19-norandrosterone and 19-noretiocholanolone in human urine after consumption of a nutritional supplement and norsteroids.

Nandrolone is one of the synthetic anabolic steroids banned in sports and has been a popular substance abused by athletes in recent years. One of its major metabolites, 19-norandrosterone (19-NA), has been used as a determinant for drug violations in sports. Current reports regarding nandrolone-positive cases have been related to intake of some nandrolone-free nutritional supplements. The aim of this study was to learn whether if a nutritional supplement sold by over-the-counter (OTC) nutritional stores could yield the same metabolic products as that of nandrolone. If so, what is (are) the substance(s) that contributed to the nandrolone metabolites? To determine the content of an OTC nutritional supplement, a tablet was dissolved in methanol, followed by N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA)-trimethyliodosilane (TMIS) derivatization prior to gas chromatography-mass spectrometry (GC-MS) analysis. The collected urine samples underwent extraction, enzymatic hydrolysis, and derivatization before the analyses of GC-MS. The results showed that seven anabolic steroids were found as contaminants in the nutritional supplement, in addition to six that were listed in the ingredients by the manufacturer. We confirmed previous reports that administration of the OTC supplement could produce a positive urine test for nandrolone metabolites. Furthermore, the results from excretion studies showed that 19-NA and 19-noretiocholanolone (19-NE) were present in urine after consuming the nutritional supplement, nandrolone, 19-nor-4-androsten-3,17-dione, 19-nor-4-androsten-3beta,17beta-diol, and 19-nor-5-androsten-3beta,17beta-diol. The 19-NA concentrations in urine were generally higher than that of 19-NE (19-NA/19-NE ratio > 1.0) especially during the early stage of excretion, that is, before 6 h post-administration. After this period of time, the concentrations of 19-NA and 19-NE fluctuated and might even have reversed (19-NA/19-NE ratio < 1.0) in their ratio, that is, higher yield in 19-NE than that in 19-NA. On the basis of this study, we postulate that some doping violations of nandrolone could be attributed by indiscriminate administration of the OTC nutritional supplements that contained 19-norsteroids.