Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice.

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Wang J, Bruin MAC, Gan C, Lebre MC, Rosing H, Beijnen JH, Schinkel AH

Brain accumulation of tivozanib is restricted by ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) in mice.

Int J Pharm. 2020 May 15;581:119277. doi: 10.1016/j.ijpharm.2020.119277. Epub 2020 Mar 28.

PubMed ID

32234426 [ View in PubMed

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Abstract

Tivozanib is a potent and selective inhibitor of VEGFR1-3, recently approved by the EMA for first-line treatment of renal cell carcinoma. We used wild-type, knockout, and transgenic mouse strains to study the effects of the drug transporters ABCB1, ABCG2, and OATP1A/1B, and of the CYP3A enzymes on the oral availability and tissue distribution of tivozanib. Tivozanib was transported by human ABCB1 and mouse Abcg2 in polarized MDCK-II cells. Upon oral administration, tivozanib showed rapid absorption and the plasma concentration-time curves showed secondary peaks in all mouse strains, suggesting enterohepatic recirculation. The brain-to-plasma ratios were significantly increased in Abcb1a/1b(-/-) (2.2-fold) and Abcb1a/1b;Abcg2(-/-) (2.6-fold) mice compared to wild-type mice, indicating a modest protective role of these transporters in the blood-brain barrier. Slco1a/1b(-/-) mice showed a 1.2-fold lower liver-to-plasma ratio than wild-type mice, suggesting a minor role of mOatp1a/1b in tivozanib liver distribution. Oral plasma pharmacokinetics of tivozanib was not significantly altered in these mouse strains, nor in Cyp3a knockout and CYP3A4-humanized mice. The modest effect of ABC transporters on tivozanib brain accumulation, if also true in humans, might mean that this drug is not strongly limited in its therapeutic efficacy against malignant lesions situated partly or completely behind the blood-brain barrier.

DrugBank Data that Cites this Article

Drugs

Tivozanib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tivozanib	Vascular endothelial growth factor receptor 1	Protein	Humans	Yes	Inhibitor	Details
Tivozanib	Vascular endothelial growth factor receptor 2	Protein	Humans	Yes	Inhibitor	Details
Tivozanib	Vascular endothelial growth factor receptor 3	Protein	Humans	Yes	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Tivozanib	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Tivozanib	P-glycoprotein 1	Protein	Humans	Unknown	Substrate	Details