The present study assessed the effect of systemic lupus erythematosus (SLE) activity, a chronic and inflammatory autoimmune disease, on the sinusoidal uptake transporter OATP1B1 using atorvastatin (ATV) as a probe drug. Fifteen healthy subjects, 13 patients with controlled SLE (SLEDAI 0–4), and 12 patients with uncontrolled SLE (SLEDAI from 6 to 15), all women, were investigated. Apparent total clearance of midazolam (MDZ), a marker of CYP3A4 activity, did not vary among the three investigated groups. The controlled and uncontrolled SLE groups showed higher plasma concentrations of MCP‐1 and TNF‐α, while the uncontrolled SLE group also showed higher plasma concentrations of IL‐10. The uncontrolled SLE group showed higher area under the curve (AUC) for ATV (60.47 (43.76–83.56) vs. 30.56 (22.69–41.15) ng⋅hour/mL) and its inactive metabolite ATV‐lactone (98.74 (74.31–131.20) vs. 49.21 (34.89–69.42) ng⋅hour/mL), and lower apparent total clearance (330.7 (239.30–457.00) vs. 654.5 (486.00–881.4) L/hour) and apparent volume of distribution (2,609 (1,607–4,234) vs. 7,159 (4,904–10,450) L), when compared to the healthy subjects group (geometric mean and 95% confidence interval). The pharmacokinetics of ATV and its metabolites did not differ between the healthy subject group and the patients with controlled SLE group. In conclusion, uncontrolled SLE increased the systemic exposure to both ATV and ATV‐lactone, inferring inhibition of OATP1B1 activity, once in vivo CYP3A4 activity assessed by oral clearance of MDZ was unaltered. The inflammatory state, not the disease itself, was responsible for the changes described in the uncontrolled SLE group as a consequence of inhibition of OATP1B1, because systemic exposure to ATV and its metabolites were not altered in patients with controlled SLE.

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Efeito do lúpus eritematoso sistêmico na atividade do transportador de influxo sinusoidal OATP1B1 avaliado com base na farmacocinética e farmacodinâmica da atorvastatina Ribeirão Preto 2018 i RESUMO CESTARI, R. N. Efeito do lúpus eritematoso sistêmico na atividade do transportador de influxo sinusoidal OATP1B1 avaliado com base na farmacocinética e farmacodinâmica da atorvastatina. 2018. 156f. Tese (Doutorado).

Lopinavir (LPV)/ritonavir (RTV) are currently the most commonly used protease inhibitors in pregnant women with HIV. LVP, a substrate of drug efflux transporter P-glycoprotein (P-gp), has a very low oral bioavailability due to the extensive metabolism by CYP3A4. However, it is coadministered with ritonavir, a potent inhibitor of CYP3A4 and P-gp. This study investigates the kinetic disposition of LPV and RTV in maternal plasma of pregnant women with HIV as well as the placental transfer of both drugs. We investigated 7 patients in the third trimester of pregnancy treated with 400 mg of LPV and 100 mg of RTV every 12 h. Serial maternal blood samples were collected up to 12 h after administration of LPV/RTV. At delivery were also collected simultaneously maternal and cord blood samples to determine the placental transfer of both drugs. The method of simultaneous analysis of LPV an RTV in plasma was developed and validated using LC-MS/MS. Plasma samples (100 µL) were spiked with antipyrine as internal standard and submitted to liquid-liquid extraction with tertbutyl methyl ether. The separation of LPV, RTV and internal standard was obtained on C18e reverse phase column with a mobile phase consisted of acetonitrile, water and formic acid (50:50:0.1, v/v/v) at a flow rate of 1.3 mL/min. The method has no matrix effect, it is linear in the range of 6.40 ng/mL to 12.50 µg/mL for LPV and 3.20 to 12.50 µg/mL for RTV and shows lower limits of quantitation of 6.40 ng/mL for LPV and 3.20 ng/mL for RTV. The coefficients of variation and relative standard errors obtained in studies of intraassay and interassay precision and accuracy were below 15% for both compounds. Pharmacokinetic analysis was performed using the WinNonlin program. The following pharmacokinetic parameters were obtained for LPV (data expressed as medians) during the third trimester of pregnancy: Cmax 14.63 µg/mL, t max 4.0 h, AUC 0-12 95.21 µg.h/mL, t 1/2 6.72 h, Cl/F 4.20 L/h and Vd/F 37.91 L. Regarding RTV, the following values were obtained: Cmax 0.64 µg/mL, t max 4.0 h, AUC 0-12 4.47 µg.h/mL, t 1/2 3.20 h, Cl/F 22.39 L/h and Vd/F 110.43 L. The umbilical vein/maternal plasma ratios were 0.11 (0.09 to 0.20) for LPV and 0.07 (0.05 to 0.12) for RTV (data presented as medians and percentiles 25-75), indicating low placental transfer of both drugs.