Yeh T K, Kang H J, Wientjes M G, Au J L
Division of Pharmaceutics and Pharmaceutical Chemistry, Ohio State University, Columbus 43210, USA.
Pharm Res. 1996 Apr;13(4):628-32. doi: 10.1023/a:1016018726327.
This study examined the pharmacokinetic interaction between 2',3'-dideoxyinosine (ddI) and pentamidine.
ddI and pentamidine are often coadministered to patients with acquired immunodeficiency syndrome, and are both associated with pancreatic toxicity. Information on potential interaction would be useful to assess the need for dose modification and the basis of the higher incidence of pancreatic toxicity associated with coadministration of the two drugs.
ddI (200 mg/kg) and pentamidine (10 mg/kg) were administered by continuous infusion to rats over 3 hr, either alone or concomitantly. Drug analysis was by high pressure liquid chromatography with UV or fluorescence detection, or by radioimmunoassay.
Pentamidine coadministration significantly increased the apparent volume of distribution at steady state of ddI from 1.4 to 3.4 l/kg (p = 0.004), and increased the mean residence time from 36.3 to 50.0 min (p = 0.015). Pentamidine enhanced the distribution of ddI from plasma into pancreas (p = 0.001) and muscle (p = 0.026). ddI distribution into spleen and liver was also increased, with differences approaching statistical significance (p = 0.08 and 0.06, respectively). In contrast, ddI coadministration did not affect the total body clearance but increased the urinary excretion and the renal clearance of pentamidine by about 5-fold (p = 0.0003).
These data indicate that pentamidine increased the distribution of ddI into pancreas and muscle, whereas ddI increased the renal elimination of pentamidine.
本研究检测了2′,3′-双脱氧肌苷（ddI）与喷他脒之间的药代动力学相互作用。
ddI和喷他脒常联合用于获得性免疫缺陷综合征患者，二者均与胰腺毒性相关。有关潜在相互作用的信息有助于评估调整剂量的必要性以及两种药物联合使用时胰腺毒性发生率较高的原因。
将ddI（200mg/kg）和喷他脒（10mg/kg）通过持续输注的方式在3小时内给予大鼠，单独给药或联合给药。采用高压液相色谱结合紫外或荧光检测，或放射免疫分析法进行药物分析。
联合给予喷他脒显著增加了ddI稳态时的表观分布容积，从1.4升/千克增至3.4升/千克（p = 0.004），并使平均驻留时间从36.3分钟延长至50.0分钟（p = 0.015）。喷他脒促进了ddI从血浆向胰腺（p = 0.001）和肌肉（p = 0.026）的分布。ddI向脾脏和肝脏的分布也有所增加，差异接近统计学意义（分别为p = 0.08和0.06）。相比之下，联合给予ddI并不影响喷他脒的总体清除率，但使喷他脒的尿排泄和肾清除率增加了约5倍（p = 0.0003）。
这些数据表明，喷他脒增加了ddI在胰腺和肌肉中的分布，而ddI增加了喷他脒的肾清除率。
