Differential changes in the pharmacokinetics of statins in collagen-induced arthritis rats
Journal
Biochemical Pharmacology
Journal Volume
142
Pages
216-228
Date Issued
2017
Author(s)
Abstract
The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins. ? 2017 Elsevier Inc.
Subjects
BDDCS; Pharmacokinetics; Rheumatoid arthritis; Statins
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; atorvastatin; creatine kinase; cytochrome P450 2C; cytochrome P450 3A; cytochrome P450 3A1; fluindostatin; messenger RNA; multidrug resistance associated protein 2; pravastatin; rosuvastatin; simvastatin; ABC transporter; Abcc2 protein, rat; collagen; cytochrome P450; hydroxymethylglutaryl coenzyme A reductase inhibitor; organic anion transporter; alanine aminotransferase blood level; animal cell; animal experiment; animal model; Article; aspartate aminotransferase blood level; blood analysis; concentration (parameters); controlled study; creatine kinase blood level; drug blood level; drug clearance; drug disposition; drug transport; enzyme metabolism; female; hepatic portal vein; liver cell; liver microsome; liver toxicity; mass spectrometry; metabolic activity assay; metabolic clearance; metabolic stability; myopathy; nonhuman; priority journal; protein expression; rat; reverse transcription polymerase chain reaction; rheumatoid arthritis; ultra performance liquid chromatography; animal; area under the curve; blood; chemically induced; dose response; enzymology; experimental arthritis; gene expression; genetics; immunology; intestine; intravenous drug administration; Lewis rat; metabolic clearance rate; metabolism; oral drug administration; tissue distribution; Administration, Oral; Animals; Area Under Curve; Arthritis, Experimental; ATP-Binding Cassette Transporters; Collagen; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Female; Gene Expression; Hepatocytes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Injections, Intravenous; Intestines; Metabolic Clearance Rate; Microsomes, Liver; Organic Anion Transporters; Rats, Inbred Lew; Tissue Distribution
Type
journal article