Journal article
A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model
The Journal of pharmacology and experimental therapeutics, Vol.371(2), pp.385-393
11/01/2019
PMID: 31420525
Abstract
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 of 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 (AUC
) 1.7-fold. Silymarin increased pitavastatin AUC
in both control and NASH animals approx. 2-fold. NASH increased pitavastatin plasma concentrations from 2 to 40 minutes, but AUC
was unchanged. The combination of silymarin and NASH had the greatest effect on pitavastatin AUC
, which increased 2.9-fold compared with control vehicle-treated animals. NASH increased the total amount of pitavastatin excreted into the bile 2.7-fold compared with control animals, whereas silymarin decreased pitavastatin biliary clearance approx. 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: Multifactorial 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.
Metrics
1 File views/ downloads
3 Record Views
Details
- Title
- A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model
- Creators
- Michelle L Montonye - Washington State University SpokaneDan-Dan Tian - Washington State University SpokaneTarana Arman - Washington State University SpokaneKatherine D Lynch - Washington State University SpokaneBruno Hagenbuch - University of Kansas Medical CenterMary F Paine - Washington State University, Department of Pharmaceutical SciencesJohn D Clarke - Washington State University, Department of Pharmaceutical Sciences
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.371(2), pp.385-393
- Academic Unit
- Department of Pharmaceutical Sciences
- Grant note
- U54 AT008909 / NCCIH NIH HHS R00 ES024455 / NIEHS NIH HHS P30 GM118247 / NIGMS NIH HHS R01 GM077336 / NIGMS NIH HHS
- Identifiers
- 99901181236301842
- Language
- English
- Resource Type
- Journal article