Fischman A J, Alpert N M, Livni E, Ray S, Sinclair I, Elmaleh D R, Weiss S, Correia J A, Webb D, Liss R
Department of Radiology, Massachusetts General Hospital, Boston.
J Pharmacol Exp Ther. 1991 Dec;259(3):1351-9.
[4-18F]Fluconazole was used to measure the pharmacokinetics of fluconazole in normal and infected animals. The biodistribution of fluconazole was determined after administration of the 18F-tracer with/without a pharmacological dose of unlabeled drug by radioactivity measurements on excised tissues. In normal rabbits and rabbits with candidal infection of the thigh, tissue concentrations of drug were determined by serial positron emission tomographic imaging. In rats, coinjection of tracer quantities of [4-18F]fluconazole with a pharmacological dose of unlabeled drug resulted in a relatively uniform distribution of radioactivity in most organs, whereas, when the 18F-tracer was injected alone, spleen, muscle and heart accumulation was decreased and liver accumulation was increased. In rabbits, this effect was less pronounced. Early accumulation of [4-18F]fluconazole was greater in infected muscle. The areas under the 2-hr uptake curves were 4.30 and 6.05 micrograms.hr.ml-1 for normal and infected tissue. A mathematical model was used to summarize the kinetics of fluconazole in normal and infected muscle. The model hypothesizes that fluconazole is compartmentalized in blood and tissue, with rate constants describing the transition between compartments. Direct measurement of the partition coefficient of fluconazole in muscle and predictions of the kinetic model were in close agreement, suggesting that fluconazole enters muscle via a passive transport mechanism. Transport rates of fluconazole, into (Kin) and out of tissue (kout), were increased in infected compared with normal muscle, possibly due to increased capillary permeability (Kin: 0.064 +/- 0.001 vs. 0.0270 +/- 0.0002, kout: 0.063 +/- 0.002 vs. 0.035 +/- 0.001).
[4-¹⁸F]氟康唑被用于测定氟康唑在正常动物和感染动物体内的药代动力学。通过对切除组织进行放射性测量，在给予¹⁸F示踪剂且有无药理剂量未标记药物的情况下，确定氟康唑的生物分布。在正常兔和大腿念珠菌感染的兔中，通过连续正电子发射断层成像确定药物的组织浓度。在大鼠中，将示踪量的[4-¹⁸F]氟康唑与药理剂量的未标记药物共同注射，导致放射性在大多数器官中分布相对均匀，而当单独注射¹⁸F示踪剂时，脾脏、肌肉和心脏的蓄积减少，肝脏的蓄积增加。在兔中，这种效应不太明显。[4-¹⁸F]氟康唑在感染肌肉中的早期蓄积更大。正常组织和感染组织在2小时摄取曲线下的面积分别为4.30和6.05微克·小时·毫升⁻¹。使用数学模型总结氟康唑在正常和感染肌肉中的动力学。该模型假设氟康唑在血液和组织中被分隔，速率常数描述各隔室之间的转换。氟康唑在肌肉中的分配系数的直接测量值与动力学模型预测值密切一致，表明氟康唑通过被动转运机制进入肌肉。与正常肌肉相比，感染肌肉中氟康唑进入（Kin）和流出组织（kout）的转运速率增加，可能是由于毛细血管通透性增加（Kin：0.064±0.001对0.0270±0.0002，kout：0.063±0.002对0.035±0.001）。
