RESUMEN
AOD9604 is a peptide consisting of the C-terminal fragment of human growth hormone from amino acids 177-191 with an additional tyrosine residue at the N-terminus of the peptide. It is reported to mimic the lipolytic properties of growth hormone without the diabetogenic side effects. Therefore, AOD9604 may be used as a performance enhancing drug and is banned by the World Anti-doping Agency (WADA). The peptide is available on several Internet websites and was recently identified in confiscated vials in the USA. To detect abuse of the peptide in athletes, a solid-phase extraction method was validated in urine with a limit of detection of 50 pg/mL. The method has good linearity, precision (<20%), specificity and recovery (62%). Six potential metabolites of the peptide were identified after incubation of AOD9604 in serum and urine. Quantification of the metabolites in serum identified a single metabolite, consisting of amino acids CRSVEGSCG, which is significantly more stable than the other metabolites or the parent compound. Screening for AOD9604 and the stable metabolite may potentially allow an increased window of detection.
Asunto(s)
Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/orina , Somatostatina/sangre , Somatostatina/orina , Detección de Abuso de Sustancias/métodos , Espectrometría de Masas en Tándem/métodos , Secuencia de Aminoácidos , Cromatografía Liquida/métodos , Doping en los Deportes , Humanos , Límite de Detección , Datos de Secuencia Molecular , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Extracción en Fase Sólida/métodos , Somatostatina/química , Somatostatina/metabolismoRESUMEN
Pharmacologic or surgical manipulation with growth hormone secretion or with the physiologic release of somatostatin and growth hormone-releasing hormone affects some rat liver enzymes, especially the sex-differentiated ones. We investigated the effects of two somatostatin analogs on several enzyme functions in six patients with carcinoid syndrome, using codeine as a probe drug. Codeine was given intravenously and its N- and O-demethylation, as well as 6-glucuronidation catalyzed by CYP3A, CYP2D6, and uridine diphosphate-glucuronosyltransferase, respectively, were studied before and during treatment with somatostatins. After 3 days of treatment with somatostatins the partial metabolic clearance of codeine by N-demethylation decreased by 21% to 64% in all patients (mean change, 44%; p < 0.05), and the clearance by O-demethylation was decreased by 20% to 69% in five of the patients (mean change in all patients, 35%; p < 0.05). In contrast, the partial clearance by 6-glucuronidation and the total systemic clearance of codeine were unchanged. Our results may be caused by the inhibition of growth hormone secretion induced by the somatostatins, inasmuch as direct metabolic interactions with these peptide drugs are improbable. The decline in CYP3A4 and CYP2D6 activity might have clinical implications when substrates of these enzymes with low therapeutic indices are combined with somatostatin analogs. Because the formation of morphine from codeine was altered, the analgesic effect of this drug may be reduced during concomitant treatment with somatostatins.
Asunto(s)
Analgésicos Opioides/farmacocinética , Codeína/farmacocinética , Citocromo P-450 CYP2D6/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Oxigenasas de Función Mixta/efectos de los fármacos , Somatostatina/análogos & derivados , Somatostatina/farmacología , Adulto , Anciano , Analgésicos Opioides/sangre , Analgésicos Opioides/orina , Codeína/sangre , Codeína/orina , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Antagonistas de Hormonas/sangre , Antagonistas de Hormonas/orina , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/metabolismo , Neoplasias/tratamiento farmacológico , Somatostatina/sangre , Somatostatina/orinaRESUMEN
Concentration of Cholecystokinin(CCK) and Somatostantin(SS) in Plasma, 24 h urine and morning urine were observed in 57 pilots (22-45 years, mean 27.9) and 60 ground crew (23-47 years, mean 30.7). The results showed that CCK level in plasma, 24 h urine and morning urine (20.14 +/- 4.15, 10.08 +/- 2.29 and 11.29 +/- 2.18 pmol/L respectively) in pilots were significantly lower than those in ground crew (22.89 +/- 3.76, 7.04 +/- 1.03, 8.10 +/- 1.94 pmol/ L respectively) and those of SS were distinctly higher than in ground crew (12.38 +/- 2.34, 6.75 +/- 1.18, 7.41 +/- 1.27pmol/L respectively). Concentration of CCK and SS in plasma were positively related to those in 24 h urine and morning urine both in pilots and ground crew. It suggests that these changes might play potential role in the pathogenesis of some diseases of digestive system in pilots.
Asunto(s)
Medicina Aeroespacial , Colecistoquinina/metabolismo , Somatostatina/metabolismo , Adulto , China , Colecistoquinina/sangre , Colecistoquinina/orina , Enfermedades Gastrointestinales/etiología , Humanos , Persona de Mediana Edad , Personal Militar , Somatostatina/sangre , Somatostatina/orinaRESUMEN
The disposition and tissue distribution of angiopeptin, a long-acting octapeptide analogue of somatostatin, were studied in rats following single iv and sc administration of the drug. Similar plasma levels and excretion values of angiopeptin were observed by using radioimmunoassay and radiolabeling techniques. Angiopeptin was absorbed fairly rapidly, with a mean peak plasma level of 25 +/- 4.1 ng/ml at 10-15 min after administration. The kinetics of angiopeptin following sc administration closely resembled those following iv administration due to rapid absorption. The pharmacokinetics of angiopeptin can be described by a two-compartment model. The plasma half-life of the drug ranged from 2.6-2.9 hr when administered sc and 1.98-2.5 hr when given iv. Distribution of angiopeptin was rapid, with the highest concentration appearing in the liver. Half-lives in the liver and bile were short. Most of the drug was excreted in the feces via the bile, while approximately 10% was excreted in the urine. Angiopeptin was also found to be secreted in the saliva. TLC and HPLC of blood, urine, feces, and bile samples did not reveal the presence of any metabolites. In conclusion, the in vivo fate of angiopeptin is characterized by little or no hepatic metabolism and rapid biliary excretion.
Asunto(s)
Antineoplásicos/farmacocinética , Oligopéptidos/farmacocinética , Somatostatina/análogos & derivados , Secuencia de Aminoácidos , Animales , Antineoplásicos/sangre , Antineoplásicos/orina , Bilis/metabolismo , Radioisótopos de Carbono , Heces/química , Mucosa Gástrica/metabolismo , Inyecciones Intravenosas , Inyecciones Subcutáneas , Radioisótopos de Yodo , Hígado/metabolismo , Masculino , Datos de Secuencia Molecular , Oligopéptidos/sangre , Oligopéptidos/orina , Péptidos Cíclicos , Radioinmunoensayo , Ratas , Ratas Endogámicas , Somatostatina/sangre , Somatostatina/farmacocinética , Somatostatina/orina , Distribución TisularRESUMEN
Timed urine collections were obtained from normal men and women for a study of somatostatin in urine. Somatostatin-14-like immunoreactivity (S-14 LI) was extracted from urine by adsorption to C-18 silica cartridges, and the extracts were analyzed by RIA directly or after gel and high pressure liquid chromatography (HPLC). S-14 LI was consistently detected in all urine samples. The mean S-14 LI content in 24-h collections in men [10.96 +/- 0.91 (+/- SE) pmol/24 h; n = 10; total volume, 1.96 +/- 0.09 L] was not significantly different from that in women (9.09 +/- 0.85 pmol/24 h; n = 10; total volume, 1.87 +/- 0.09 L). Gel chromatography of 24-h urine collections revealed three major peaks of S-14 LI coeluting with S-14, S-28, and a 12,000 mol wt species corresponding to prosomatostatin. HPLC analysis confirmed the presence of S-14, S-28, and the 12,000 mol wt form and additionally revealed a major fourth peak of 3,000 mol wt, closely related to S-28. Immunoreactivity corresponding to [Des,Ala1]S-14 (S-13) was identified by HPLC coelution with synthetic S-13 and reactivity in a centrally, but not N-terminally directed, S-14 RIA. The relative proportions of the different HPLC peaks varied considerably during the 24-h period. S-14 and S-28 were excreted preferentially during the day, whereas the 12,000 and 3,000 mol wt forms were excreted preferentially at night. The ingestion of a mixed meal evoked parallel increases in plasma S-14 LI and urinary S-14 LI excretion in six normal subjects. We conclude that the principal circulating forms of S-14 LI (S-14, S-28, S-13, and pro-S) are present in urine and that the measurement of urinary S-14 LI could provide a reliable index of integrated plasma S-14 LI concentrations.
Asunto(s)
Somatostatina/orina , Adulto , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Femenino , Humanos , MasculinoRESUMEN
Using a previously described radioimmunoassay for growth hormone release inhibiting hormone (GH-RIH), the presence of GH-RIH-like immunoreactivity in urine has been characterized by demonstrating mobility identical to synthetic GH-RIH standard on two sephadex gel chromatographic systems, and parallelism of dilutions of the sephadex fractions with synthetic GH-RIH. Furthermore, 74% of the sephadex fraction cross-reacting in the immunoassay bound to antibody conjugated to sepharose and could be eluted by 1 M acetic acid. This immunospecific eluate showed identity with synthetic GH-RIH on both ion exchange and thin layer chromatography. Thus GH-RIH-like immunoreactivity is present in normal urine; this may have potential relevance in the search for a physiological role for this peptide.