Pharmacokinetic assessment of cooperative efflux of the multitargeted kinase inhibitor ponatinib across the blood-brain barrier

Janice K. Laramy, Minjee Kim, Karen E. Parrish, Jann N Sarkaria, William F. Elmquist

Research output: Contribution to journalArticle

Abstract

A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(2/2)Bcrp1(2/2)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(2/2) or Mdr1a/b(2/2)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(2/2)Bcrp1(2/2) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.

Original languageEnglish (US)
Pages (from-to)249-261
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume365
Issue number2
DOIs
StatePublished - May 1 2018

Fingerprint

Blood-Brain Barrier
Phosphotransferases
Pharmacokinetics
Brain
Knockout Mice
P-Glycoprotein
Breast Neoplasms
Pharmaceutical Preparations
ponatinib
Brain Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Pharmacokinetic assessment of cooperative efflux of the multitargeted kinase inhibitor ponatinib across the blood-brain barrier. / Laramy, Janice K.; Kim, Minjee; Parrish, Karen E.; Sarkaria, Jann N; Elmquist, William F.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 365, No. 2, 01.05.2018, p. 249-261.

Research output: Contribution to journalArticle

@article{58e016eace44445090335dbcd007fd6e,
title = "Pharmacokinetic assessment of cooperative efflux of the multitargeted kinase inhibitor ponatinib across the blood-brain barrier",
abstract = "A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(2/2)Bcrp1(2/2)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(2/2) or Mdr1a/b(2/2)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(2/2)Bcrp1(2/2) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.",
author = "Laramy, {Janice K.} and Minjee Kim and Parrish, {Karen E.} and Sarkaria, {Jann N} and Elmquist, {William F.}",
year = "2018",
month = "5",
day = "1",
doi = "10.1124/jpet.117.246116",
language = "English (US)",
volume = "365",
pages = "249--261",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Pharmacokinetic assessment of cooperative efflux of the multitargeted kinase inhibitor ponatinib across the blood-brain barrier

AU - Laramy, Janice K.

AU - Kim, Minjee

AU - Parrish, Karen E.

AU - Sarkaria, Jann N

AU - Elmquist, William F.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(2/2)Bcrp1(2/2)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(2/2) or Mdr1a/b(2/2)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(2/2)Bcrp1(2/2) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.

AB - A compartmental blood-brain barrier (BBB) model describing drug transport across the BBB was implemented to evaluate the influence of efflux transporters on the rate and extent of the multikinase inhibitor ponatinib penetration across the BBB. In vivo pharmacokinetic studies in wild-type and transporter knockout mice showed that two major BBB efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), cooperate to modulate the brain exposure of ponatinib. The total and unbound (free) brain-to-plasma ratios were approximately 15-fold higher in the triple knockout mice lacking both P-gp and Bcrp [Mdr1a/b(2/2)Bcrp1(2/2)] compared with the wild-type mice. The triple knockout mice had a greater than an additive increase in the brain exposure of ponatinib when compared with single knockout mice [Bcrp1(2/2) or Mdr1a/b(2/2)], suggesting functional compensation of transporter-mediated drug efflux. Based on the BBB model characterizing the observed brain and plasma concentration-time profiles, the brain exit rate constant and clearance out of the brain were approximately 15-fold higher in the wild-type compared with Mdr1a/b(2/2)Bcrp1(2/2) mice, resulting in a significant increase in the mean transit time (the average time spent by ponatinib in the brain in a single passage) in the absence of efflux transporters (P-gp and Bcrp). This study characterized transporter-mediated drug efflux from the brain, a process that reduces the duration and extent of ponatinib exposure in the brain and has critical implications for the use of targeted drug delivery for brain tumors.

UR - http://www.scopus.com/inward/record.url?scp=85045009788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045009788&partnerID=8YFLogxK

U2 - 10.1124/jpet.117.246116

DO - 10.1124/jpet.117.246116

M3 - Article

VL - 365

SP - 249

EP - 261

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -