Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.
Pharmacokinetics of 2',3'-dideoxyadenosine in dogs.
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2,3-双脱氧腺苷在狗体内的药代动力学。
DOI：
10.1007/bf00175083
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发表时间：
1991
影响因子：
3.4
通讯作者：
Tomaszewski,JE
中科院分区：
文献类型：
--
作者：
Wientjes,MG;Placke,ME;Chang,MJ;Page,JG;Kluwe,WM;Tomaszewski,JE
研究了2’，3’-二脱氧腺苷（ddAdo）和2’-3’-二脱氧腺苷（ddIno）在犬体内静脉给药和长期静脉滴注后的药代动力学。ddAdo被迅速脱去为ddIno，而ddAdo的血浆浓度仅为ddIno浓度的一小部分。犬体内对ddAdo的总清除率超过文献中对心排血量的值，表明其代谢速度极快，存在肝外代谢。尿排泄未改变的ddAdo是次要的消除途径（约1%）。假设dado完全转化为ddIno，确定ddIno的药代动力学。ddIno消除呈剂量依赖性，个体动物的全身清除率为4 ~ 55 ml/min/kg。在大多数给药途径后，血浆半衰期约为30分钟，但在接受500mg /kg大静脉剂量的两只动物中，半衰期增加到约60分钟。ddIno在一定程度上渗透到脑脊液中，浓度达到血浆浓度的3-11%。未改变的ddIno尿排泄约占ddAdo给药剂量的20%，而尿酸和次黄嘌呤是次要的尿代谢产物。超过其体外最低病毒抑制浓度（2.4 μg/mL）的浓度可在血浆中安全维持10天。在脑脊液浓度为12 ~ 17 μLg/mL的情况下，在10天内出现剂量限制的骨髓抑制和肠道毒性。在无呕吐的情况下，口服ddAdo以ddIno吸收，生物利用度为28% ~ 93%。这些研究表明，ddAdo在体内转化为ddIno的速度很快，并支持在进一步的药物开发中选择ddIno而不是ddAdo。
The pharmacokinetics of 2′,3′-dideoxyadenosine (ddAdo) and 2′-3′-dideoxyinosine (ddIno) were determined after intravenous bolus administration and long-term intravenous infusion of ddAdo in dogs. ddAdo was rapidly deaminated to ddIno and ddAdo plasma concentrations were only a fraction of ddIno concentrations. The total body clearance of ddAdo exceeded the literature value for the cardiac output of the dog, indicating an extremely rapid metabolism, and the existence of extrahepatic metabolism. Urinary excretion of unchanged ddAdo was a minor route of elimination (∼ 1%). The pharmacokinetics of ddIno was determined assuming complete conversions of ddAdo to ddIno. ddIno elimination was dose-dependent with total body clearance ranging from 4 to 55 ml/min/kg in individual animals. The plasma half-life was approximately 30 min after most routes of administration, but increased to approximately 60 min in two animals receiving a large intravenous dose of 500 mg/kg. ddIno penetrated into the cerebrospinal fluid to a limited extent, reaching concentrations of 3–11% of those in plasma. Urinary excretion of unchanged ddIno accounted for approximately 20% of the administered dose of ddAdo, while uric acid and hypoxanthine were minor urinary metabolites.Concentrations exceeding thein vitrominimal viral inhibitory concentration (2.4 μg/mL) could be safely maintained in plasma for a 10-day period. Infusions which gave cerebrospinal fluid concentrations of 12 to 17 μLg/mL resulted in dose limiting myelosuppression and intestinal toxicity, after less than 10 days of infusion. Orally administered ddAdo was absorbed as ddIno, with bioavailabilities ranging from 28 to 93% in experiments where no emesis occurred. These studies indicate the rapidin vivoconversion of ddAdo to ddIno, and support the selection of ddIno over ddAdo for further drug development.