Rheumatoid arthritis downregulates the drug transporter OATP1B1: Fluvastatin as a probe

Author(s)

Caris, Juciene Aparecida ^[1] ; de Lima Benzi, Jhohann Richard ^[1] ; Lima de Souza, Flavio Falcao ^[2] ; Ribeiro de Oliveira, Rene Donizeti ^[2] ; Donadi, Eduardo Antonio ^[2] ; Lanchote, Vera Lucia ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Anal Food Sci & Toxicol, Ave Cafe Sn Campus USP, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Div Rheumatol, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: European Journal of Pharmaceutical Sciences; v. 146, APR 15 2020.
• Web of Science Citations: 0

Abstract

Aims: Rheumatoid arthritis (RA) is a long term autoimmune inflammatory disease characterized by high autoantibody production and cytokine release, especially IL-6 and TNF-alpha. Some clinical studies have shown the effect of RA on CYP metabolism. However, the effect of RA on the drug transporter OATP1B1 remains a gap. Methods: Patients with RA under pharmacological treatment (n = 10) and healthy volunteers (n = 15) treated for seven consecutive days with racemic fluvastatin (20, 40, or 80 mg/24 h) were investigated. Serial blood samples were collected during the last dose interval. All participants were assessed for cytokine profile and CYP2C9 genotype. Results: Patients with RA showed increased plasma concentrations of IFN-gamma and TNF-alpha up to two and four times, respectively, when compared to healthy volunteers, whereas CYP2C9 activity based on genotype was considered normal or slightly reduced for both investigated groups. When compared to healthy volunteers, patients with RA presented higher values (median and 25th-75th percentiles) of normalized AUC for 20 mg dose (250 {[}114-405] vs. 96.7 {[}78.1-131] ng h mL(-1) for ( - )-3S,5R-fluvastatin and 163 {[}96.9-325] vs. 83.1 {[}61.7-107] ng-h-mL(-1) for ( + )-3R,5S-fluvastatin) and lower values of CL/F (40.9 {[}24.5-89.1] vs. 103 {[}75.9-128] L-h(-1) for (-)-3S,5R-fluvastatin and 61.4 {[}30.6-103] vs. 120 {[}93.0-162] L-h(-1) for ( + )-3R,5S-fluvastatin) and V/F (73.0 {[}28.5-117] vs. 143 {[}108-221] L for ( - )-3S,5R-fluvastatin and 93.9 {[}32.7-116] vs. 153 {[}122-234] L for ( + )-3R,5S-fluvastatin) for both enantiomers. Conclusion: The lower values of CL/F and V/F for both fluvastatin enantiomers in RA patients suggest that the inflammatory disease downregulates the sinusoidal drug transporter OATP1B1, the rate-determining step in the hepatic clearance of fluvastatin. (AU)

• FAPESP's process: 14/02802-0 - Influence of rheumatoid arthritis on pharmacokinetics and pharmacokinetics-pharmacodynamics (PK-PD) of the enantiomers of fluvastatin
• Grantee: Juciene Aparecida Caris
• Support Opportunities: Scholarships in Brazil - Post-Doctoral