Walker R F, Codd E E, Barone F C, Nelson A H, Goodwin T, Campbell S A
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Life Sci. 1990;47(1):29-36. doi: 10.1016/0024-3205(90)90563-7.
The purpose of this study was to evaluate the growth hormone (GH) releasing activity of orally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in rats, dogs and monkeys. Rats were administered GHRP-6 orally by gavage or parenterally through femoral artery catheters. Blood was collected before and after GHRP-6 administration for estimation of plasma GH and comparison of GH changes resulting from enteral and parenteral administration of the peptide. GHRP-6 was administered to dogs intravenously (i.v.) through cephalic vein catheters, intragastrically (i.g.) through esophagostomy tubes or intraduodenally (i.d.) through vascular access ports, and blood was collected before and after peptide administration for estimation of plasma GH. Cynomolgus monkeys were administered GHRP-6 i.g., and blood was collected from abdominal aorta for estimation of changes in plasma GH. Enteral activity of GHRP-6 was observed in all 3 species tested. In rats, ED50's for enteral and parenteral administration of GHRP-6 were 4 mg/kg and 28 micrograms/kg, respectively. Thus in rats, enterally administered GHRP-6 was 0.7% as bioactive as the parenterally administered peptide. In dogs GHRP-6 was slightly less potent than in rats, with ED50's for i.g. and i.v. administration approximately 15 mg/kg and 125 micrograms/kg, respectively. However, enteral potency of GHRP-6 in dogs was 0.8% of parenteral potency, and thus, comparable to that in rats. Additionally, comparison of plasma GH levels following i.g. vs i.d. administration in dogs suggested greater activity by the i.d. route. Monkeys were the species most sensitive to enterally administered GHRP-6, with plasma GH increased in those receiving i.g. doses as low as 0.3 mg/kg and an ED50 of 0.75 mg/kg compared to 4 and 15 mg/kg in rats and dogs, respectively. The results of this study demonstrate that GHRP-6 releases GH when administered directly into the gastrointestinal tract. Although enteral activity is approximately 1% of parenteral activity, GHRP-6 is potent, especially in primates which require relatively low doses to provoke GH release. These data suggest that orally active GHRP-6 may provide a practical therapeutic alternative to parenterally administered peptides such as GHRH, especially if enteral activity is enhanced with appropriate formulation.
本研究的目的是评估口服His-D-Trp-Ala-Trp-D-Phe-Lys-NH2（GHRP-6，SK&F 110679）在大鼠、犬和猴体内的生长激素（GH）释放活性。通过灌胃法给大鼠口服GHRP-6，或经股动脉导管进行非肠道给药。在给予GHRP-6前后采集血液，以测定血浆GH，并比较该肽经肠道和非肠道给药后GH的变化。通过头静脉导管给犬静脉注射（i.v.）GHRP-6，通过食管造口管进行胃内给药（i.g.），或通过血管通路端口进行十二指肠内给药（i.d.），并在给予肽前后采集血液以测定血浆GH。给食蟹猴进行胃内给药GHRP-6，并从腹主动脉采集血液以评估血浆GH的变化。在所有测试的3个物种中均观察到了GHRP-6的肠道活性。在大鼠中，GHRP-6经肠道和非肠道给药的半数有效剂量（ED50）分别为4 mg/kg和28 μg/kg。因此，在大鼠中，经肠道给药的GHRP-6的生物活性是经非肠道给药肽的0.7%。在犬中，GHRP-6的效力略低于大鼠，胃内给药和静脉注射的ED50分别约为15 mg/kg和125 μg/kg。然而，GHRP-6在犬体内的肠道效力是非肠道效力的0.8%，因此与大鼠相当。此外，犬胃内给药与十二指肠内给药后血浆GH水平的比较表明，十二指肠内给药途径的活性更高。猴是对经肠道给药的GHRP-6最敏感的物种，接受低至0.3 mg/kg胃内剂量的猴血浆GH升高，其ED50为0.75 mg/kg，而大鼠和犬分别为4 mg/kg和15 mg/kg。本研究结果表明，直接将GHRP-6注入胃肠道时可释放GH。尽管肠道活性约为非肠道活性的1%，但GHRP-6效力很强，尤其是在灵长类动物中，它们只需相对较低的剂量就能刺激GH释放。这些数据表明，口服活性GHRP-6可能为诸如生长激素释放激素（GHRH）等非肠道给药肽提供一种实用的治疗替代方案，特别是如果通过适当的制剂增强肠道活性的话。
