St. Stephen's Centre, Chelsea and Westminster Hospital, London, United Kingdom.
Antimicrob Agents Chemother. 2013 Aug;57(8):3640-4. doi: 10.1128/AAC.00357-13. Epub 2013 May 20.
Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.
阿扎那韦（ATV）可通过抑制 UDP 葡萄糖醛酸基转移酶 1A1（UGT1A1）导致非结合型高胆红素血症（HBR）升高。硫酸锌（ZnSO4）可降低 Gilbert 综合征患者的非结合型高胆红素血症。我们评估了单次和 14 天给药后总胆红素、结合胆红素和非结合胆红素的变化，以及对阿扎那韦药代动力学（PK）的影响。HIV 患者在含有阿扎那韦/利托那韦（ATV/r）的方案下稳定，总胆红素水平>25mmol/L，每天接受 125mg 的硫酸锌（ZnSO4）治疗，为期 14 天，每天 1 次。在 ATV/r 剂量前（第 1 阶段）、2、4、6、8 和 24 小时后（第 2 阶段）以及在 ZnSO4 开始前（第 1 阶段）、单次剂量后（第 2 阶段）和 14 天后（第 3 阶段）测量 ATV/r 和胆红素浓度。评估有无 ZnSO4 时胆红素和 ATV/r 浓度的变化，采用几何平均比（GMR）和 90%置信区间（CI；我们使用第 1 阶段作为参考）。16 名男性患者完成了研究，保持病毒学抑制；硫酸锌（ZnSO4）耐受性良好。第 2 阶段总胆红素 C（max）和 AUC（0-24）下降 16%和 17%，第 3 阶段下降 20%。尽管结合胆红素无显著变化，但非结合胆红素 C（max）和 AUC（0-24）较低（第 2 阶段下降 17%和 19%；第 3 阶段下降 20%和 23%）。ATV 的 C（谷）、C（max）和 AUC（0-24）的 GMR（90%CI）分别为 0.74（0.62 至 0.89）、0.82（0.70 至 0.97）和 0.78（0.70 至 0.88）。硫酸锌（ZnSO4）的摄入可降低总胆红素和非结合胆红素，并适度降低阿扎那韦的暴露量。硫酸锌（ZnSO4）的补充可能对治疗某些患者的阿扎那韦相关 HBR有用。
