| Erythropoietin (EPO) is a glycoprotein secreted by the kidneys, which can bind to EPO receptor expressed in the surface of red blood cells, and stimulate the proliferation and differentiation of the red blood cells in the bone marrow. Previous studies show that EPO is one of growth factors with mutil-functions. EPO-RmRNA, EPO-R protein and EPO-EPO·R are widely distubited in the non Erythropoietin cells and organs such as brain, cardiovascular, liver, gastrointestinal tract, insulin. Since the United States formally approved the drug (recombinant Human EPO -rHuEPO) in 1989, rHuEPO has been widely used in clinical treatment of various types of anemia. However, the drug of rHuEPO in current market has short half-life (4-8 hours) and mutil-injections are need in clinical practiacal. Therefore, in order to reduce the suffering of the patients caused by mutil-injection the development of a new rHuEPO with longer biological half-life are needed. Recently, a long-lasting recombinant human erythropoietin (LL-rHuEPO) was newly developed by a research institute of China. The aim of the present study is to study the Preclinical pharmacokinetics, distribution and excretion of the newly developed LL-rHuEPO in rats using 125I isotope tracing techniques. The results are as follows:1. Pharmacokinetics of LL-rHuEPO in rats:After single iv injection (1, 2, 3 ug/kg LL-rHuEPO) in rats, the main pharmacokinetic parameters were taken by the method of calculating statistics: AUC (0-48h) was: 192.137, 329.434, 641.622 (ug / L / h); Cmax was: 12.1, 18.874, 29.398 (ug / L). AUC, Cmax are dose related. t1/2z was: 20.457 h, 25.053h, 20.409h.After single im injection(1,2,3 ug/kg LL-rHuEPO) in rats, the main pharmacokinetics parameters were as follows: CLz / F from 0.001到0.006 L / h / kg; t1/2z from 25.258 to 287.91 hours, but most remain at between 40 to 60hours; MRTs (0-72h) are the similar among 3 different treatments, ranging from 33.664 to 34.883 hours with dose-related and dose-proportional increases of Cmax and AUC ( 0-72h) values.2. Distribution of LL-rHuEPO in rats: LL-rHuEPO concentration in different tissue at the certain time after im administration (at the dose of 2ug/kg) was mensurated. After administration of 8h, 24h, 48h: LL-rHuEPO are mainly distributed in the muscle of injection site, plasma, bone marrow. Much less of LL-rHuEPO were found in the tissue of heart, kidney, liver, and .the tissue of brain, small intestine and large intestine with the least LL-rHuEPO. 3. Excretion of LL-rHuEPO in rats:LL-rHuEPO was given to SD rats by iv administration at the dose of 2ug/kg. About 22.09% of the injected amount was excreted in feces and urine within 11das, of which 20.7%, 1.39% was excreted in urine and feces, respectively.Conclusions:1. After iv administration of LL-rHuEPO to rats (at the dose of 1, 2, 3 ug / kg, respectively), its elimination half-life was 20h to 25h.2. After im administration of LL-rHuEPO to rats (at the dose of 1, 2, 3 ug / kg, respectively), its elimination half-life mainly changed from 30h to 60h.3. The elimination half-life of LL-rHuEPO was obviously longer than rHuEPO.4. Bioavailability of LL-rHuEPO im injection was high (about 90%).5. Distribution of LL-rHuEPO following im administration in rats was extensive. Bone marrow was its main functionary poisition.6. LL-rHuEPO was mainly excreted by urine via kidney. And it could experience widely metabolism and could be eliminated by transforming metabolites.LL-rHuEPO; isotope tracer; pharmacokinetics; distribution; excretion...
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