Saitoh Akihiko, Sarles Elizabeth, Capparelli Edmund, Aweeka Francesca, Kovacs Andrea, Burchett Sandra K, Wiznia Andrew, Nachman Sharon, Fenton Terence, Spector Stephen A
Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, California 92093-0672, USA.
AIDS. 2007 Oct 18;21(16):2191-9. doi: 10.1097/QAD.0b013e3282ef9695.
Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited.
In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases.
NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01).
The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.
细胞色素P450 2B6（CYP2B6）-G516T基因型与肝脏CYP2B6活性改变及依非韦伦药代动力学相关，但CYP2B6-G516T基因型与血浆和脑脊液（CSF）中奈韦拉平（NVP）药代动力学之间的关系尚不明确。
在126名来自儿童艾滋病临床试验组（PACTG）366和377队列、接受NVP和蛋白酶抑制剂治疗的儿童中，采用实时聚合酶链反应（PCR）分析CYP2B6和ATP结合盒转运体B家族成员1（ABCB1）基因多态性。收集血浆NVP药代动力学数据和临床资料，并对患有HIV相关神经系统疾病的儿童脑脊液中NVP水平进行评估。
CYP2B6-516-T/T基因型（纯合变异型，n = 14）儿童的NVP口服清除率为1.6 l/h per m² , 与-G/G基因型（野生型，n = 49，P = 0.002）儿童的2.3 l/h per m² 和-G/T基因型（杂合变异型，n = 63，P = 0.008）儿童的2.1 l/h per m² 相比，显著降低。此外，从基线到第12周，-T/T基因型儿童的CD4+ T细胞百分比显著增加（+9.0%），而-G/G基因型儿童增加了+3.2%（P = 0.01），-G/T基因型儿童增加了+5.0%（P = 0.04）。在第24周时仍保持相同趋势。虽然ABCB1-C3435T基因型不影响血浆NVP药代动力学（P = 0.39），但ABCB1-3435-C/T或-T/T基因型（n = 9）儿童的NVP脑脊液与血浆比值显著高于ABCB1-3435-C/C基因型（n = 5）儿童（0.62比0.43，P = 0.01）。
CYP2B6-G516T基因型改变儿童NVP药代动力学及对含NVP的高效抗逆转录病毒治疗（HAART）方案的免疫反应。这些数据表明，CYP2B6-G516T是一个重要的基因变异，可改变含NVP的HAART方案的药代动力学和反应。
