Systemic Lupus Erythematosus Activity Affects the Sinusoidal Uptake Transporter OATP1B1 Evaluated by the Pharmacokinetics of Atorvastatin

Abstract

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.

The Cytokine Release Syndrome and/or the Proinflammatory Cytokines as Underlying Mechanisms of Downregulation of Drug Metabolism and Drug Transport: A Systematic Review of the Clinical Pharmacokinetics of Victim Drugs of this Drug–Disease Interaction Under Different Clinical Conditions

“…Overall, 64 full-text articles were assessed for eligibility, and 42 of these were excluded according to the following criteria: lack of quantitative PK data (18 studies), reviews (11 studies), preclinical studies (ten studies), and a lack of data on inflammatory biomarkers (three studies). After manual screening of reference lists of included studies, four more studies were identified, thus the final review included 26 original studies assessing the PK behavior of victim drugs [ 15 – 40 ] (Fig. 2 ).…”

“…Overall, only two studies were retrieved (Table 1 of the ESM) [ 39 , 40 ], and both investigated the inhibitory effect that pro-inflammatory cytokines may have on the OAPT1B1-mediated transport of statins during chronic inflammatory conditions. The first was a case-control PK study that tested the potential influence of a chronic inflammation state on the PK behavior of fluvastatin by comparing the profile of this probe drug of the hepatic sinusoidal OATP1B1 activity between 15 patients with RA and ten healthy volunteers [ 39 ].…”

“…The second was a case-control PK study that assessed the potential influence of chronic inflammatory status on the PK behavior of probe drugs of both OATP1B1 (atorvastatin) and CYP3A4 (midazolam) by comparing the PK profiles of these two drugs in healthy volunteers ( n = 15), and in patients with controlled ( n = 13) or uncontrolled ( n = 12) systemic lupus erythematosus (SLE) [ 40 ]. Patients with uncontrolled SLE had TNF-α levels and monocyte chemoattractant protein-1 levels that were significantly higher compared with healthy volunteers.…”

“…Among these 26 studies, 15 assessed the influence of cytokine modulation on the pharmacokinetics of drugs that behave as substrates of the CYP system during acute or chronic inflammatory conditions [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]; nine assessed the impact of anti-inflammatory biological agents in counteracting the inhibitory effect of pro-inflammatory cytokines on the pharmacokinetics of drugs that behave as substrates of CYP during acute or chronic inflammatory conditions [30][31][32][33][34][35][36][37][38]; two assessed the impact of the influence of cytokine modulation on the pharmacokinetics of drugs that behave as substrates of transporters during acute or chronic inflammatory conditions [39,40]. Details of clinical characteristics and PK parameters retrieved in these three subgroups of studies are provided in Tables 1, 2, and 3 and Table 1 of the Electronic Supplementary Material (ESM), respectively.…”

“…In regard to the first point, it could be speculated that the increased exposure to statins, cyclosporin, midazolam, and darunavir shown during acute or chronic inflammatory conditions compared with baseline [ 15 , 25 , 28 , 39 , 40 ] could lead to drug-related adverse events and/or toxicity when these victim drugs of CYP3A4-mediated metabolism and/or of OATP1B1-mediated uptake are administered to patients having high levels of pro-inflammatory cytokines. Additionally, the weak-to-moderate downregulation of the CYP2C9 and CYP2C19 activity caused by pro-inflammatory cytokines has been investigated only for some probe drugs.…”