Lindstrom T D, Althaus W A, Ruterbories K J, Kau D
Department of Drug Metabolism and Disposition, Eli Lilly and Company, Indianapolis, Indiana.
J Pharmacol Exp Ther. 1990 Mar;252(3):1117-24.
The plasma pharmacokinetics of the monoclonal antibody-vinca conjugate KS 1/4-desacetylvinblastine hydrazide (DAVLB-hyd; [3H]LY203725) have been evaluated in rats (17 mg/kg) and monkeys (15 mg/kg) after i.v. dosing. Plasma concentrations of radioactivity 1 hr after dosing were higher in monkeys than in rats. The biphasic elimination of radioactivity in rats was characterized by half-lives (T1/2) of 10 and 143 hr, whereas the elimination of radioactivity in monkeys was characterized by T1/2 values of 11 and 66 hr. Plasma total antibody and radioactivity concentrations were similar within 6 (rat) and 24 (monkey) hr after dosing; however, total antibody concentrations were greater than radioactivity concentrations thereafter, indicating the presence of free antibody in the plasma. Plasma elimination T1/2 values and areas under the curve of total antibody in rats and monkeys were greater than those of radioactivity. The presence of free antibody implies the presence of free DAVLB-hyd; however, plasma concentrations of free DAVLB-hyd were at least 3 orders of magnitude less than those of radioactivity in both species. The T1/2 of free DAVLB-hyd in plasma of LY203725 dosed monkeys was 16 hr. Hydrolysis of the conjugate to yield free DAVLB-hyd was observed upon incubation of conjugate with rat plasma in vitro. Administration of DAVLB-hyd to rats resulted in a rapid initial decrease in plasma DAVLB-hyd followed by a slower (T1/2 = 1.4 hr) elimination rate. Fecal excretion was the predominant mode of elimination of radioactivity in both rats and monkeys dosed with [3H]LY203725.
在静脉注射给药后，已对单克隆抗体-长春花属植物缀合物KS 1/4-去乙酰长春碱酰肼（DAVLB-hyd；[3H]LY203725）在大鼠（17mg/kg）和猴子（15mg/kg）体内的血浆药代动力学进行了评估。给药1小时后，猴子体内放射性物质的血浆浓度高于大鼠。大鼠体内放射性物质的双相消除特征为半衰期（T1/2）分别为10小时和143小时，而猴子体内放射性物质的消除特征为T1/2值分别为11小时和66小时。给药后6小时（大鼠）和24小时（猴子）内，血浆总抗体和放射性浓度相似；然而，此后总抗体浓度大于放射性浓度，表明血浆中存在游离抗体。大鼠和猴子体内血浆消除T1/2值以及总抗体的曲线下面积均大于放射性物质的相应值。游离抗体的存在意味着游离DAVLB-hyd的存在；然而，在两个物种中，游离DAVLB-hyd的血浆浓度至少比放射性物质的血浆浓度低3个数量级。LY203725给药猴子血浆中游离DAVLB-hyd的T1/2为16小时。在体外将缀合物与大鼠血浆孵育时，观察到缀合物水解产生游离DAVLB-hyd。给大鼠注射DAVLB-hyd后，血浆中DAVLB-hyd最初迅速下降，随后消除速率减慢（T1/2 = 1.4小时）。在给予[3H]LY203725的大鼠和猴子中，粪便排泄是放射性物质消除的主要方式。
