Joshi Anand, Guo Jianxia, Holleran Julianne L, Kiesel Brian, Taylor Sarah, Christner Susan, Parise Robert A, Miller Brian M, Ivy S Percy, Chu Edward, Venkataramanan Raman, Beumer Jan H
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Cancer Therapeutics Program, UPMC Hillman Cancer Center, Hillman Research Pavilion, Room G27E 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA.
Cancer Chemother Pharmacol. 2020 Oct;86(4):535-545. doi: 10.1007/s00280-020-04145-6. Epub 2020 Sep 18.
Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol.
Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC-MS/MS.
In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes.
Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions.
卡铂剂量是根据肾功能计算的，通常使用基于肌酐的不完善公式进行估算。碘海醇用于测量肾小球滤过率（GFR），并能计算出更合适的卡铂剂量。为了解决在化疗过程中给予碘海醇可能影响该治疗的潜在担忧，我们对碘海醇进行了体外和体内药代动力学药物 - 药物相互作用评估。
以60mg/kg的剂量静脉注射卡铂给雌性小鼠，同时或不同时给予300mg/kg的碘海醇。通过原子吸收分光光度法定量血浆超滤液、肾脏和骨髓中的铂。在有或没有300μg/mL碘海醇的情况下，通过液相色谱 - 串联质谱法评估紫杉醇微粒体代谢、吉西他滨胞质代谢以及CYP和UGT探针的代谢。
体内卡铂暴露不受碘海醇联合给药的显著影响（铂AUC联合用药与单独用药相比：血浆超滤液1791对1920μg/mL·min；肾脏8367对9757μg/g·min；骨髓12.7对12.7μg/mg - 蛋白·min）。紫杉醇微粒体代谢未受影响（联合用药与单独用药相比：6 - α - OH - 紫杉醇38.3对39.4ng/mL/60min；3 - p - OH - 紫杉醇26.2对27.7ng/mL/60min）。吉西他滨人胞质消除未受影响（AUC联合用药与单独使用吉西他滨相比：dFdU 24.1对23.7μg/mL/30min）。碘海醇对人肝微粒体中的CYP和UGT酶无相关抑制作用。
碘海醇不太可能影响卡铂、紫杉醇、吉西他滨或与卡铂治疗联合使用的其他药物的临床药代动力学。用碘海醇测量GFR以更好地调整卡铂剂量不太可能通过药代动力学药物 - 药物相互作用改变化疗的安全性或疗效。
