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CC BY-NC V4.0, Open Access
Journal article
Goldenseal-mediated inhibition of intestinal uptake transporters decreases metformin systemic exposure in mice
Drug metabolism and disposition, Vol.51(11), pp.1483-1489
11/01/2023
PMID: 37562957
Abstract
Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin C
and AUC by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (-)-β-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using HEK293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC
: 4.9, 13.1, and 5.8 μM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (-)-β-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin C
by 31% and 25%, respectively, and had no effect on half-life. Berberine and (-)-β-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction
A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal-metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2.
Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters
and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.
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Details
- Title
- Goldenseal-mediated inhibition of intestinal uptake transporters decreases metformin systemic exposure in mice
- Creators
- Victoria O Oyanna - Washington State University SpokaneKenisha Y Garcia-Torres - Washington State UniversityBaron J Bechtold - Washington State University SpokaneKatherine D Lynch - Washington State University SpokaneM Ridge Call - Pharmaceutical Sciences, Washington State University, United StatesMiklós Horváth - Solvo BiotechnologyPreston K Manwill - University of North Carolina at GreensboroTyler N Graf - University of North Carolina at GreensboroNadja B Cech - University of North Carolina, United StatesNicholas H Oberlies - University of North Carolina at GreensboroMary F Paine - Washington State University, Department of Pharmaceutical SciencesJohn D Clarke - Washington State University, Department of Pharmaceutical Sciences
- Publication Details
- Drug metabolism and disposition, Vol.51(11), pp.1483-1489
- Academic Unit
- Department of Pharmaceutical Sciences
- Identifiers
- 99901181236901842
- Language
- English
- Resource Type
- Journal article