Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V111294A in healthy volunteers
Pharmacokinetic and pharmacodynamic profile following oral administration of the phosphodiesterase (PDE)4 inhibitor V111294A in healthy volunteers
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DOI：
10.1046/j.1365-2125.2002.01682.x
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发表时间：
2002-11-01
影响因子：
3.4
通讯作者：
O'Connor, BJ
中科院分区：
文献类型：
--
作者：
Gale, DD;Landells, LJ;O'Connor, BJ
目的评价新型PDE 4抑制剂V11294 A（3-（3-环戊氧基-4-甲氧基苄基）-6-乙氨基-8-异丙基-3H嘌呤盐酸盐）在健康男性志愿者中的药代动力学和药效学特征。在经口给药前和给药后0.5、1、2、2.5、3、4、6、9、12、18和24 h采集血样，用于测定V11294 A的血浆浓度。结果单次口服300 mg V11294 A后，V11294 A及其活性代谢产物V10332的血药浓度均达到C-max（ng ml（-1）;平均值+/- s.d.; 1398 298，1000 400）分别在2.63 +/- 0.79和5.9 +/- 2.3小时后。对于V11294 A和V10332，t（1/2）分别为9.7 +/- 3.9和9.5 +/- 1.7 h，AUC（0，无穷大）分别为18100 +/- 6100和18600 8500 ng ml（-1）h。给药3 h时，V11294 A和V10332（3-（3-环戊氧基-4-甲氧基-苄基）-8-异丙基-3H-嘌呤-6-基胺）的血浆浓度分别为1300 +/- 330和860 +/- 300 ng/ml（-1），分别是其抑制TNT释放和增殖的体外IC（50）的7倍和3倍。用V11294 A处理导致摄入后3小时（P < 0.001）和24小时（P < 0.05）脂多糖（LPS）诱导的TNT释放显著减少。在安慰剂治疗后，次最大浓度LPS（4 ng/ml）引起的TNT释放量（pmol ml-1）没有显著改变（给药前681 +/- 68 vs给药后3 h 773 +/- 109，P = 0.27）。相比之下，V11294 A处理后释放的TNT量显著降低（给药前778 +/- 87 vs给药后3 h 566 +/- 72，P = 0.02）。在给药前，植物血凝素（PHA）刺激全血中[H-3]-胸苷的掺入。V11294 A在3 h时抑制PHA诱导的细胞增殖（P < 0.05）。结论健康志愿者单次口服300 mg V11294 A后，血浆中V11294 A浓度足以抑制体外炎性细胞的活化，并可持续至少24 h而无任何不良反应。
Aims To assess the pharmacokinetic and pharmacodynamic profile of the novel PDE4 inhibitor V11294A (3-(3-cyclopentyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H purine hydrochloride) in healthy male volunteers.Methods This was a double-blind, single dose, randomized crossover study in eight healthy volunteers who received a single oral, fasting dose of V11294A (300 mg) or placebo. Blood samples were taken before and 0.5, 1, 2, 2.5, 3, 4, 6, 9, 12, 18 and 24 h after oral dosing for determination of plasma concentrations of V11294A. Blood samples were also taken before and 3 and 24 h after dosing for the assessment of the effect of V11294A on mononuclear cell proliferation and tumour necrosis factor (TNF) release in whole blood.Results Following a single oral dose of 300 mg V11294A, plasma concentrations of V11294A and its active metabolite V10332 reached C-max (ng ml(-1); mean +/- s.d.; 1398 298, 1000 400, respectively) after 2.63 +/- 0.79 and 5.9 +/- 2.3 h, respectively. For V11294A and V10332, t(1/2) were 9.7 +/- 3.9 and 9.5 +/- 1.7 h, and AUC(0,infinity) were 18100 +/- 6100 and 18600 8500 ng ml(-1) h, respectively. At 3 h dosing, plasma concentrations of V11294A and V10332 (3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-3H-purin-6-ylamine) were 1300 +/- 330 and 860 +/- 300 ng ml(-1), 7 and 3 times their in vitro IC(50)s for inhibition of TNT release and proliferation, respectively. Treatment with V11294A resulted in a significant reduction of lipopolysaccharide (LPS)-induced TNT release at 3 h (P < 0.001) and at 24 h (P < 0.05) post ingestion. The amount of TNT released (pmol ml(-1)) in response to a submaximal concentration of LPS (4 ng nil 1) was not significantly altered following placebo treatment (before 681 +/- 68 vs 3 h postdose 773 +/- 109, P = 0.27). In contrast, there was a significant reduction in the amount of TNT released following treatment with V11294A (before 778 +/- 87 vs 3 h postdose 566 +/- 72, P = 0.02). Phytohaemagluttinin (PHA) stimulated the incorporation of [H-3]-thymidine in whole blood prior to drug administration. V11294A inhibited the PHA-induced proliferation at 3 h (P < 0.05). No adverse reactions were noted following single oral administration of V11294A.Conclusions A single oral 300 mg dose of V11294A administered to healthy volunteers results in plasma concentrations adequate to inhibit activation of inflammatory cells ex vivo, which persists for at least 24 h without any adverse reactions.