Pego Álef Machado Gomes, Marques Maria Paula, Moreira Fernanda de Lima, Paz Tiago, Tarozzo Maria Martha de Barros, Mattos Rogério Pereira, Dos Santos Melli Patrícia Pereira, Duarte Geraldo, Cavalli Ricardo Carvalho, Lanchote Vera Lucia
Department of Clinical Analysis, Food Science and Toxicology, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Department of Drugs and Medicines, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
J Clin Pharmacol. 2024 Aug 27. doi: 10.1002/jcph.6125.
This study investigates the influence of pregnancy on the in vivo activity of the intestinal P-glycoprotein (P-gp) and hepatic organic anion transporters polypeptide (OATP/BCRP) using, respectively, fexofenadine and rosuvastatin as probe drugs. Eleven healthy participants were investigated during the third trimester of pregnancy (Phase 1, 28 to 38 weeks of gestation) and in the postpartum period (Phase 2, 8 to 12 weeks postpartum). In both phases, after administration of a single oral dose of fexofenadine (60 mg) and rosuvastatin (5 mg), serial blood samples were collected for up to 24 h. Rosuvastatin and fexofenadine in plasma were analyzed by LC-MS/MS using previously validated methods. The pharmacokinetic parameters of fexofenadine and rosuvastatin (Phoenix WinNonLin software) with normal distribution (Shapiro-Wilk test) are presented as geometric mean and 90% confidence interval. Phases 1 and 2 were compared using the t test (P < .05). Fexofexadine AUC values do not differ (P-value: .0715) between Phase 1 (641.9 ng h/mL [500.6-823.1]) and Phase 2 (823.8 ng h/mL [641.5-1057.6]) showing that pregnancy (third trimester) does not alter intestinal P-gp activity. However, rosuvastatin AUC values are higher (P-value: .00005) in Phase 1 (18.7 ng h/mL [13.3-26.4]) when compared to Phase 2 (9.5 ng h/mL [6.7-13.4]), suggesting inhibition of OATP1B1/OATP1B3 transporters. In conclusion, pregnancy assessed during the third trimester does not alter the intestinal P-gp activity but reduces the activity of hepatic OATP1B1/OATP1B3 transporters. Therefore, adjustments in dosage regimens may be necessary for drugs with low therapeutic index, substrates of the OATP1B1/OATP1B3 transporters, administered during the third trimester of pregnancy.
本研究分别使用非索非那定和瑞舒伐他汀作为探针药物，调查妊娠对肠道P-糖蛋白（P-gp）和肝脏有机阴离子转运多肽（OATP/BCRP）体内活性的影响。对11名健康参与者在妊娠晚期（第1阶段，妊娠28至38周）和产后时期（第2阶段，产后8至12周）进行了调查。在两个阶段中，单次口服非索非那定（60mg）和瑞舒伐他汀（5mg）后，连续采集血样长达24小时。采用先前验证的方法，通过液相色谱-串联质谱法（LC-MS/MS）分析血浆中的瑞舒伐他汀和非索非那定。非索非那定和瑞舒伐他汀的药代动力学参数（Phoenix WinNonLin软件）呈正态分布（Shapiro-Wilk检验），以几何均值和90%置信区间表示。使用t检验对第1阶段和第2阶段进行比较（P<0.05）。第1阶段（641.9ng h/mL[500.6-823.1]）和第2阶段（823.8ng h/mL[641.5-1057.6]）之间的非索非那定AUC值无差异（P值：0.0715），表明妊娠晚期不会改变肠道P-gp活性。然而，与第2阶段（9.5ng h/mL[6.7-13.4]）相比，第1阶段（18.7ng h/mL[13.3-26.4]）的瑞舒伐他汀AUC值更高（P值：0.00005）,提示OATP1B1/OATP1B3转运体受到抑制。总之，妊娠晚期评估显示，妊娠不会改变肠道P-gp活性，但会降低肝脏OATP1B1/OATP1B3转运体的活性。因此，对于治疗指数较低、且为OATP1B1/OATP1B3转运体底物的药物，在妊娠晚期给药时可能需要调整给药方案。
