Kattel Krishna, Evande Ruby, Tan Chalet, Mondal Goutam, Grem Jean L, Mahato Ram I
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Br J Clin Pharmacol. 2015 Aug;80(2):267-75. doi: 10.1111/bcp.12620. Epub 2015 Jun 11.
This study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer.
Nelfinavir was administered orally to patients for over 10 days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C191, CYP2C192 and CYP2C19*3 were determined by the polymerase chain reaction-restriction fragment length polymorphism method.
Pharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean Cmax of nelfinavir in CYP2C19*1/1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) µg ml(-1) , while that of CYP2C191/2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) µg ml(-1) at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean Cmax of CYP2C191/1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) µg ml(-1) , while those of CYP2C191/2 patients were 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) µg ml(-1) at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentration-time curve (AUC(0,12 h)) values of nelfinavir for CYP2C191/1 patients were 28.90 ± 1.27 and 38.90 ± 4.99 µg ml(-1) ·h and for CYP2C191/2 patients, AUC(0,12 h) was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) µg ml(-1) ·h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The Cmax of nelfinavir was significantly higher (P <0.05) in CYP2C191/*2 patients but there was no statistical difference in AUC(0,12 h).
CYP2C19*1/*2 genotype modestly affected the pharmacokinetic profiles of nelfinavir and M8 in patients with locally advanced pancreatic cancer.
本研究评估了CYP2C19基因多态性对胰腺癌患者中奈非那韦及其代谢产物M8药代动力学的影响。
对患者口服奈非那韦超过10天。通过高效液相色谱法测定奈非那韦和M8的血浆浓度。采用聚合酶链反应-限制性片段长度多态性方法测定CYP2C191、CYP2C192和CYP2C19*3的基因型。
奈非那韦和M8的药代动力学特征表现为个体间差异较大。在每天两次给予625和1250 mg奈非那韦的剂量下，CYP2C19*1/1患者中奈非那韦的平均Cmax分别为3.89±0.40（n = 3）和5.12±0.41（n = 30）μg/ml，而CYP2C191/2患者中奈非那韦的平均Cmax分别为3.60（n = 1）和6.14±0.31（n = 5）μg/ml。对于M8代谢产物，在每天两次给予625和1250 mg奈非那韦的剂量下，CYP2C191/1患者中M8的平均Cmax分别为1.06±0.06（n = 3）和1.58±0.27（n = 30）μg/ml，而CYP2C191/2患者中M8的平均Cmax分别为1.01（n = 1）和1.23±0.15（n = 5）μg/ml。CYP2C191/1患者中奈非那韦的血浆浓度-时间曲线下面积（AUC(0,12 h)）值分别为28.90±1.27和38.90±4.99 μg/ml·h，CYP2C19!/2患者中奈非那韦的AUC(0,12 h)在每天两次给予625和1250 mg奈非那韦的剂量下分别为28.20（n = 1）和40.22±3.17（n = 5）μg/ml·h。CYP2C191/*2患者中奈非那韦的Cmax显著更高（P<0.05），但AUC(0,12 h)无统计学差异。
CYP2C19*1/*2基因型对局部晚期胰腺癌患者中奈非那韦和M8的药代动力学特征有适度影响。
