RT Journal Article
SR Electronic
T1 A pharmacokinetic natural product-disease-drug interaction: a double hit of silymarin and nonalcoholic steatohepatitis on hepatic transporters in a rat model
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.260489
DO 10.1124/jpet.119.260489
A1 Michelle L Montonye
A1 Dan-Dan Tian
A1 Tarana Arman
A1 Katherine D Lynch
A1 Bruno Hagenbuch
A1 Mary F Paine
A1 John D Clarke
YR 2019
UL http://jpet.aspetjournals.org/content/early/2019/08/16/jpet.119.260489.abstract
AB Patients with nonalcoholic steatohepatitis (NASH) exhibit altered hepatic protein expression of metabolizing enzymes and transporters and altered xenobiotic pharmacokinetics. The botanical natural product silymarin, which has been investigated as a treatment for NASH, contains flavonolignans that inhibit organic anion transporting polypeptide (OATP) transporter function. The purpose of this study was to assess the individual and combined effects of NASH and silymarin on the disposition of the model OATP substrate pitavastatin. Male Sprague Dawley rats were fed a control or a methionine and choline deficient diet (NASH model) for 8 weeks. Silymarin (10 mg/kg) or vehicle, followed by pitavastatin (0.5 mg/kg), were administered intravenously, and the pharmacokinetics were determined. NASH increased mean total flavonolignan area under the plasma concentration-time curve (AUC0-120min) 1.7-fold. Silymarin increased pitavastatin AUC0-120min in both control and NASH animals ~2-fold. NASH increased pitavastatin plasma concentrations from 2-40 minutes, but AUC0-120min was unchanged. The combination of silymarin and NASH had the greatest effect on pitavastatin AUC0-120min, which increased 2.9-fold compared to control vehicle-treated animals. NASH increased the total amount of pitavastatin excreted into the bile 2.7-fold compared to control animals, whereas silymarin decreased pitavastatin biliary clearance ~3-fold in both control and NASH animals. This double hit of NASH and silymarin on hepatic uptake transporters is another example of a multifactorial pharmacokinetic interaction that may have a greater impact on drug disposition than each hit alone.SIGNIFICANCE STATEMENT Multi-factorial effects on xenobiotic pharmacokinetics are within the next frontier for precision medicine research and clinical application. The combination of silymarin and NASH is a probable clinical scenario that can affect drug uptake, liver concentrations, biliary elimination, and ultimately, efficacy and toxicity.