Khalil Hadeel A, Elnaggar Mai M, Belal Tarek S, El-Yazbi Ahmed F, Hamdy Dalia A
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Eur J Pharm Sci. 2016 Aug 25;91:190-5. doi: 10.1016/j.ejps.2016.05.009. Epub 2016 May 11.
Posaconazole (PSZ), lipophilic antifungal drug, is used for prophylactic purposes in immunocompromised patients. Our aim is to study its pharmacokinetics and tissue distribution in different elevated lipoprotein levels in rat.
To study PSZ pharmacokinetics and protein binding, rats (n=30) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by i.p. injection of (1g/kg) poloxamer 407 in rats. Serial blood samples were collected for 72h p.o. PSZ (40mg/kg). PSZ unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits. To study tissue distribution, rats (n=64) were allocated into NL and HL groups. After p.o. administration of PSZ 40mg/kg, blood samples were collected, lungs and liver tissues were extracted over 72h.
Orally dosed rats showed two distinct Cmax peaks reflecting PSZ enterohepatic circulation. The incremental increase in lipoprotein levels have resulted in significant decrease in PSZ unbound fraction, a significant increase in Cmax1 and the AUC0-24h (NL=IHL<HL) and a significant decrease in PSZ terminal phase half-life (NL<IHL<HL). However, AUC0-∞ and weight normalized Cl/F were not significantly different among groups. The liver and lung PSZ uptake were decreased by hyperlipidemia resulting in lower Cmax, AUC0-8h and delayed Tmax values within those tissues. However, AUC0-72h was similar between NL and HL groups.
Poloxamer induced lipoprotein level elevation caused alterations in the PSZ pharmacokinetics and decreased its hepatic and pulmonary uptake. This raises few concerns about its activity and possible drug interactions as a prophylactic therapy in hyperlipidemic immunocompromised populations.
泊沙康唑（PSZ）是一种亲脂性抗真菌药物，用于免疫功能低下患者的预防治疗。我们的目的是研究其在大鼠不同脂蛋白水平升高情况下的药代动力学和组织分布。
为研究PSZ的药代动力学和蛋白结合情况，将大鼠（n = 30）分为三组，即正常血脂组（NL）、中度高脂血症组（IHL）和重度高脂血症组（HL）。通过腹腔注射（1g/kg）泊洛沙姆407诱导大鼠高脂血症。口服PSZ（40mg/kg）后72小时内采集系列血样。使用超滤试剂盒测定NL、IHL和HL血浆中PSZ的未结合分数。为研究组织分布，将大鼠（n = 64）分为NL组和HL组。口服给予PSZ 40mg/kg后，采集血样，在72小时内提取肺和肝组织。
口服给药的大鼠显示出两个不同的Cmax峰，反映了PSZ的肠肝循环。脂蛋白水平的逐渐升高导致PSZ未结合分数显著降低，Cmax1和AUC0 - 24小时显著增加（NL = IHL < HL），PSZ终末相半衰期显著缩短（NL < IHL < HL）。然而，AUC0 - ∞和体重标准化的Cl/F在各组之间无显著差异。高脂血症导致肝脏和肺对PSZ的摄取减少，从而使这些组织中的Cmax、AUC0 - 8小时降低，Tmax值延迟。然而，NL组和HL组之间的AUC0 - 72小时相似。
泊洛沙姆诱导的脂蛋白水平升高导致PSZ药代动力学改变，并降低其肝脏和肺部摄取。这引发了对其在高脂血症免疫功能低下人群中作为预防治疗的活性和可能的药物相互作用的一些担忧。
