Carlson R P, Hartman D A, Ochalski S J, Zimmerman J L, Glaser K B
Abbott Laboratories, Abbott Park, IL 60064, USA.
Inflamm Res. 1998 Aug;47(8):339-44. doi: 10.1007/s000110050339.
To determine whole blood levels of sirolimus, a macrolide antibiotic in the rat developing adjuvant arthritis (AA) model after dosing orally with two different vehicles, and whether combinational doses of sirolimus and cyclosporin A (CsA) produced additive or synergistic inhibitory effects in this model.
Male Lewis rats (150-180g).
Arthritis was induced by the injection (0.5 mg/ rat) of heat-killed Mycobacterium butyricum suspended in light mineral oil. Drugs were administered orally either in fine suspension (0.5% Tween 80) or in emulsion (phosal 50 PG in 1% Tween 80) at doses of 0.1 to 5 mg/kg in a 7 day, MWF or daily regimen.
Paw volumes (ml) were measured by automated mercury plethysmograph and sirolimus concentrations in whole blood were quantitated by liquid chromatography/ mass spectroscopy.
At 72h (7 days after adjuvant) after receiving the third oral dose (4.5 mg/kg p.o.), the phosal vehicle resulted in higher sirolimus blood levels (2.5 ng/ml) than in Tween 80 (1.6 ng/ml). After the rats received the last oral dose on day 14, (7 total doses of sirolimus at 4.5 mg/kg) the sirolimus blood levels (2h after the last dose) were about 2 times higher for the phosal dosed rats (9.8 ng/ml) compared to Tween 80 dosed rats (4.6ng/ml). Even 24h after the last dose, sirolimus blood levels were still elevated in the phosal dosed rats (0.8 ng/ml) relative to 0.5% Tween 80 dosed rats (0.5 ng/ml). At day 16 in the rat developing model, sirolimus, when given in phosal vehicle, produced an ED50 of 0.28 mg/ kg (i.e. inhibition of uninjected paw edema) that was about 5.5 times lower than using 0.5% Tween 80 as the suspending agent (ED50 = 1.6mg/kg). When combining sirolimus and CsA using precalculated doses for producing an additive effect in this adjuvant model, an additive inhibitory effect on uninjected paw edema was observed at equal combinational doses of 0.5 and 2 mg/kg, respectively.
The phosal vehicle used in administering sirolimus increases the absorption and whole blood levels in the rat and the elevated blood levels correlated positively with the therapeutic effect in the rat developing AA model. In addition, combination therapy using sirolimus and CsA produced an additive effect in rat developing AA.
在大鼠佐剂性关节炎（AA）模型中，测定经两种不同溶媒口服给药后西罗莫司（一种大环内酯类抗生素）的全血水平，以及西罗莫司与环孢素A（CsA）联合用药在该模型中是否产生相加或协同抑制作用。
雄性Lewis大鼠（150 - 180g）。
通过注射（0.5mg/只大鼠）悬浮于轻质矿物油中的热灭活丁酸分枝杆菌诱导关节炎。药物以细悬浮液（0.5%吐温80）或乳剂（1%吐温80中的磷酸酯50 PG）口服给药，剂量为0.1至5mg/kg，给药方案为每周一、三、五或每日给药，共7天。
用自动汞体积描记仪测量爪体积（ml），通过液相色谱/质谱法定量全血中西罗莫司的浓度。
在接受第三次口服剂量（4.5mg/kg口服）72小时（佐剂注射后7天）后，磷酸酯溶媒导致的西罗莫司血药水平（2.5ng/ml）高于吐温80溶媒组（1.6ng/ml）。在第14天大鼠接受最后一次口服剂量后（西罗莫司共7次剂量，每次4.5mg/kg），与吐温80溶媒组给药的大鼠（4.6ng/ml）相比，磷酸酯溶媒组给药的大鼠末次给药后2小时的西罗莫司血药水平（9.8ng/ml）高出约2倍。即使在末次给药后24小时，磷酸酯溶媒组给药的大鼠西罗莫司血药水平（0.8ng/ml）相对于0.5%吐温80溶媒组给药的大鼠（0.5ng/ml）仍有所升高。在大鼠发病模型的第16天，以磷酸酯溶媒给药时，西罗莫司产生的半数有效剂量（ED50）为0.28mg/kg（即对未注射爪水肿的抑制作用），比使用0.5%吐温80作为悬浮剂时（ED50 = 1.6mg/kg）低约5.5倍。在该佐剂模型中，当以预先计算的剂量联合使用西罗莫司和CsA以产生相加作用时，在分别为0.5和2mg/kg的相等联合剂量下观察到对未注射爪水肿的相加抑制作用。
用于给药西罗莫司的磷酸酯溶媒可增加大鼠体内的吸收和全血水平，升高的血药水平与大鼠佐剂性关节炎发病模型中的治疗效果呈正相关。此外，西罗莫司与CsA联合治疗在大鼠佐剂性关节炎发病模型中产生了相加作用。
