Phamacokinetics of Sustained-Release Formulation of Growth Hormone in Beagle Dogs

Kim, Duk Hee; Shin, Hye Jung; Kim, Sun Jin; Hahn, Sei Kwang; Kim, Myung Jin

Abstract

sodium hyaluronate in beagle dogs.
METHODS
In group 1, hGH(Eutropin, r-hGH) 0.29mg/kg was injected subcutaneously to 6 beagle dogs everyday for 7 days. In group 2, 1mg/kg in sustained- release formulation using sodium hyaluronate(SR-hGH), was injected subcutaneously to 6 beagle dogs. In group 3, 2mg/kg of the same formulation(SR-hGH) was injected subcutaneously to 6 beagle dogs. Blood samplings were done for the measurement of GH and IGF-1 concentrations with ELISA kit(Diagnostic Systems laboratories, Inc., USA)
RESULTS
GH concentration in group 1 was below 0.5ng/ml before injection and elevated to 98.1+/-15.7 at 1 hr, 124.2+/-15 at 2 hr, 57.8+/-18.1 at 4 hr, 23.8+/-4.8 at 6hr, 10.8+/-3.7 at 8 hr, 2.8+/-1.6 at 10 hr, 1.0+/-0.7 at 12 hr, and 0.5+/-0.1ng/ml at 24hr after injection. Peak GH concentration was observed in 2 hr and thereafter decreased progressively and returned to basal level at 10 hr after injection. From the 2nd day GH concentration was measured only at 6 hr after daily GH injection, indicating the values of 20.9+/-8.7, 16.2+/-14.9, 23.1+/-8.5, 34.3+/-9.9, 16.1+/-7.0, and 21.8+/-13.0ng/ml at 2nd, 3rd, 4th, 5th 6th, and 7th day, respectively. GH concentrations in group 2(SR- hGH 1mg/kg) were 136.7+/-22.8 at 1hr, 149.3+/-29.9 at 2hr, 110.6+/-17.8 at 4hr, 103.7+/-18.2 at 6hr, 108.3+/-21.0 at 8hr, 91.4+/-21.4 at 10hr, 79.6+/-15.9 at 12hr, 23.7+/-8.3 at 24hr, 5.5+/-1.5 at 30hr, 0.7+/-0.2 at 48hr, 1.4+/-1.4 at 54hr, and 0.5+/-0.1ng/ml at 72hr after injection. GH concentration was elevated above the basal level for 72hr with the peak at 2hr after injection of SR-hGH of 1mg/kg. GH concentrations in group 3(SR-hGH 2.0mg/kg) were 196.7+/-45.2 at 1hr, 219.4+/-39.8 at 2hr, 198.1+/-38.0 at 4hr, 196.0+/-31.4 at 6hr, 179.2+/-28.3 at 8hr, 151.8+/-19.5 at 10hr, 141.3+/-23.1 at 12hr, 72.9+/-14.7 at 24hr, 43.7+/-14.2 at 30hr, 3.8+/-1.6 at 48hr, 1.6+/-0.5 at 54hr, 0.8+/-0.5 at 72hr, 0.5+/-0.1 at 78hr, and 0.5+/-0.2ng/ml at 120hr. Peak GH concentration occurred at 2hr after injection and remained high concentration till 72hr and returned to basal level thereafter. IGF-1 concentrations in group 1 changed from 190.5+/-68.1ng/ml before injection, to 326.4+/-96.2, 346.4+/-79, 391.4+/-86.9, 417.0+/-96.1, 422.1+/-92.0, 429.9+/-86.4, and 478.0+/-90.2ng/ml at 12hr, 30hr, 54hr, 78hr, 102hr, 126hr, and 150hr, respectively. IGF-1 concentrations in group 2 were 128.5+/-37.0 ng/ml before and 268.0+/-64.2, 307.6+/-63.1, 374.8+/-55.3, 335.5+/-39.4, 301.9+/-44.8, 288.5+/-42.5, 272.8+/-51.8, 273.9+/-46.0, 251.1+/-40.9, and 239.2+/-45.0ng/ml at 24hr, 30hr, 48hr, 54hr, 72hr, 78hr, 96hr, 102hr, 126hr, and 150hr, respectively after injection. Peak IGF-1 concentration was measured at 48hr and remained in high concentration till 150hr after injection. IGF-1 concentrations in group 3 were 116.0+/-68.9ng/ml before and 365.5+/-118.6, 400.0+/-135.1, 463.6+/-138, 450.2+/-140.0, 337.2+/-122.4, 301.4+/-113.4, 236.3+/-89.1, 226.3+/-75.5, 148.9+/-55.2, and 129.8 48.4ng/ml at 24hr, 30hr, 48hr, 54hr, 72hr, 78hr, 96hr, 102hr, 126hr, and 150hr, respectively after injection. Peak IGF-1 concentration was at 48hr and remained in high concentration till 150 hr after injection. There was no significant difference in IGF-I conc between group I and group 3.
CONCLUSION
Sustained-release form(1mg or 2mg/kg) of hGH with sodium hyaluronate released GH for 72 hours with the peak level at 2 hours and higher concentration of IGF-I above baseline maintained for 150 hour after injection with peak level at 48 hour. There was no difference in IGF-1 concentration between SR-hGH 1mg/kg and 2mg/kg injection. So sustained release form 1mg/kg will be more effective for GH therapy as weekly injection mode. More extensive study is needed to permit for new therapeutic application.