Inhibitory effects of chemotherapeutics on human organic anion transporter hOAT4
May Fern Toh1, Wonmo Suh1, Haoxun Wang1
1Departments of Pharmaceutics and Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers University NJ, USA.
Abstract:
Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters which play critical roles in the body disposition of clinically important drugs. hOAT4 is expressed in the kidney and placenta. In the current study, we examined the inhibitory effects of 101 anticancer drugs from a clinical drug library on hOAT4 transport activity. The studies were carried out in hOAT4-expressing human kidney HEK-293 cells and human placenta BeWo cells. Among these drugs, only chlorambucil and cabazitaxel demonstrated more than 50% cis-inhibitory effect on hOAT4-mediated uptake of (3)H-labeled estrone sulfate, a prototypical substrate for the transporter. The IC50 values for chlorambucil and cabazitaxel were 44.28 and 3.5 µM respectively. Dixon plot analysis revealed that inhibition by chlorambucil was competitive with a Ki = 55.73 µM whereas inhibition by cabazitaxel was non-competitive with a Ki = 1.78 µM. Our results demonstrated that chlorambucil and cabazitaxel were inhibitors of hOAT4. Furthermore, by comparing our data with clinically relevant exposures of these drugs, we conclude that the propensity for chlorambucil and cabazitaxel to cause drug-drug interaction through inhibition of hOAT4 is low.
Insights
Chlorambucil and cabazitaxel inhibit human organic anion transporter 4 (hOAT4). Although potent inhibitors, their clinical drug interaction potential via hOAT4 is low due to low drug concentrations.
Area of Science:
- Pharmacology
- Molecular Biology
- Drug Metabolism
Background:
- Human organic anion transporter 4 (hOAT4) is crucial for drug disposition.
- hOAT4 is expressed in vital organs like the kidney and placenta.
Purpose of the Study:
- To investigate the inhibitory effects of 101 clinical anticancer drugs on hOAT4.
- To identify which anticancer drugs significantly inhibit hOAT4 transport activity.
Main Methods:
- Utilized hOAT4-expressing HEK-293 and BeWo cells.
- Assessed inhibition of (3)H-estrone sulfate uptake.
- Determined IC50 and Ki values using Dixon plot analysis.
Main Results:
- Chlorambucil and cabazitaxel were identified as inhibitors of hOAT4.
- Chlorambucil exhibited competitive inhibition (Ki = 55.73 µM).
- Cabazitaxel showed non-competitive inhibition (Ki = 1.78 µM).
Conclusions:
- Chlorambucil and cabazitaxel are confirmed inhibitors of hOAT4.
- The risk of drug-drug interactions mediated by hOAT4 inhibition is low for these drugs at clinical concentrations.
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