Sinko P J, Smith C L, McWhorter L T, Stern W, Wagner E, Gilligan J P
Department of Pharmaceutics, College of Pharmacy, Rutgers University, Piscataway, NJ 08855-0789, USA.
J Pharm Sci. 1995 Nov;84(11):1374-8. doi: 10.1002/jps.2600841120.
Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postmenopausal osteoporosis, and hypercalcemia due to malignancy. In this study, recombinant sCT (rsCT) was administered intravenously (iv), subcutaneously (sc), and intraduodenally (id.) in rats to evaluate pharmacodynamic (PD) response as a measure of rsCT bioavailability (F) and to test the feasibility of delivering rsCT orally. rsCT pharmacokinetics were linear throughout the range of iv and sc doses studied. Following sc administration, F ranged from 11.2% to 23.1% and was linear. The absorption of rsCT after id. administration was low (0.022%); however, a significant lowering of serum calcium concentrations was observed. Serum calcium lowering was nonlinear and saturable after sc administration with the minimum dose required for maximum calcium lowering (Dmin/max) equal to 10.2 ng and a maximal response of 426.8 mg min/dL. Using Dmin/max as the reference dose, absolute Fs were recalculated using PD response after id. administration of 1 and 2 mg of rsCT and were 0.040% and 0.029%, respectively. Substantial overestimates of F were obtained when the reference dose was not properly selected. While the absorption of rsCT was low, the significant lowering of serum calcium levels suggests that oral delivery of sCT is feasible. The results of these studies also suggest that PD response is useful in assessing the oral bioavailability of peptides; however, when PD response is saturable, as is the case for rsCT, the reference dose should be carefully selected in order to avoid overestimates of F.
鲑鱼降钙素（sCT）是一种治疗性肽，用于治疗佩吉特氏病、绝经后骨质疏松症以及恶性肿瘤引起的高钙血症。在本研究中，将重组sCT（rsCT）通过静脉内（iv）、皮下（sc）和十二指肠内（id.）给药于大鼠，以评估药效学（PD）反应，作为rsCT生物利用度（F）的一种衡量指标，并测试口服rsCT的可行性。在所研究的iv和sc剂量范围内，rsCT的药代动力学呈线性。sc给药后，F范围为11.2%至23.1%，且呈线性。id.给药后rsCT的吸收较低（0.022%）；然而，观察到血清钙浓度有显著降低。sc给药后血清钙降低呈非线性且具有饱和性，最大钙降低所需的最小剂量（Dmin/max）等于10.2 ng，最大反应为426.8 mg min/dL。以Dmin/max作为参考剂量，在id.给予1 mg和2 mg rsCT后，使用PD反应重新计算绝对F值，分别为0.040%和0.029%。当未正确选择参考剂量时，会得到对F的大幅高估。虽然rsCT的吸收较低，但血清钙水平的显著降低表明sCT口服给药是可行的。这些研究结果还表明，PD反应在评估肽的口服生物利用度方面是有用的；然而，当PD反应具有饱和性时，如rsCT的情况，应仔细选择参考剂量，以避免对F的高估。
