Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice

doi:10.1021/js9901763

Journal of Pharmaceutical Sciences

Volume 88, Issue 12, December 1999, Pages 1281-1287

https://doi.org/10.1021/js9901763 Get rights and content

Abstract

To determine the contribution of the mdr1a gene product to digoxin pharmacokinetics, we constructed a physiologically based pharmacokinetic model for digoxin in mdr1a (−/−) and mdr1a (+/+) mice. After intravenous administration, total body clearance and tissue-to-plasma concentration ratios for muscle and heart were decreased in mdr1a (−/−) mice as compared with mdr1a (+/+) mice, and in particular, the digoxin concentration in the brain was 68-fold higher than that in mdr1a (+/+) mice at 12 h. On the other hand, mdr1a gene disruption did not change the contributions of renal and bile clearances to total clearance, the plasma protein binding, or the blood-to-plasma partition coefficient. Brain concentration–time profiles in mdr1a (+/+) and mdr1a (−/−) mice showed a different pattern from those in plasma and other tissues, indicating digoxin accumulation in the brain tissue. Because there was no difference in the uptake or release of digoxin by brain tissue slices from the two types of mice, we assumed the brain tissue compartment to consist of two parts (a well-stirred part with influx and efflux clearance and an accumulative part). Simulation with this model gave excellent agreement with observation when active efflux clearance across the blood+brain barrier was assumed to be zero in mdr1a (−/−) mice. The observations in other tissues in both types of mice were also well simulated.

References and Notes (30)

A. Tsuji et al.
P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells
Life Sci.
(1992)
A.H. Schinkel et al.
Multidrug resistance and the role of P-glycoprotein knockout mice
Eur. J. Cancer
(1995)
A.H. Schinkel et al.
Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs
Cell
(1994)
L.I. Harrison et al.
Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat
J. Pharm. Sci.
(1977)
P. Borst et al.
Classical and novel forms of multidrug resistance and the physiological functions of P-glycoproteins in mammals
Pharmacol. Ther.
(1993)
Y. Kamimoto et al.
The function of Gp170, the multidrug resistant gene product, in rat liver canalicular membrane vesicle
J. Biol. Chem.
(1989)
S. Hsing et al.
The function of Gp170, the multidrug resistance gene product, in the brush border of rat intestinal mucosa
Gastroenterology
(1992)
K. Ueda et al.
Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone
J. Biol. Chem.
(1992)
A. Tsuji et al.
Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein
Biochem. Pharmacol.
(1993)
T. Tatsuta et al.
Functional involvement of P-glycoprotein in blood-brain barrier
J. Biol. Chem.
(1992)

T. Ohnishi et al.

In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier

Biochem. Pharmacol.

(1995)

I. Tamai et al.

Drug delivery through the blood-brain barrier

Adv. Drug Deliv. Rev.

(1996)

A. Tsuji et al.

Blood-brain barrier function of P-glycoprotein

Adv. Drug Deliv. Rev.

(1997)

F. Thiebaut et al.

Cellular localization of the multidrug resistance gene product in normal human tissues

Proc. Natl. Acad. Sci. U.S.A.

(1987)

J.M. Croop et al.

The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues

Mol. Cell. Biol.

(1989)

Cited by (90)

Quantitative Targeted Absolute Proteomics for 28 Transporters in Brush-Border and Basolateral Membrane Fractions of Rat Kidney
2016, Journal of Pharmaceutical Sciences
Citation Excerpt :
It is considered that organic anion transporter (oat) 1 and oat3 mainly contribute to the uptake of anionic drugs by epithelial cells from blood.15 The BBM also expresses many transporters, including multidrug resistance protein (mdr) 1a/P-glycoprotein (P-gp), breast cancer resistance protein (bcrp), and multidrug resistance-associated protein (mrp) 4, which have been shown to contribute to drug transport by means of studies in gene-knockout mice.2,4,16 However, the differences in average transport activities among different transporters are poorly understood, in contrast to BLM transporters.
The purpose of the present study was to determine the absolute protein expression levels of various transporters in renal brush-border membrane (BBM) and basolateral membrane (BLM) fractions, in order to understand the quantitative differences in average transport activities among different transporters at each cellular membrane. BBM and BLM fractions of rat kidney were prepared and digested with trypsin, and simultaneous absolute quantification of 28 transporters and a BLM marker, Na⁺/K⁺-ATPase, was performed using our established quantitative-targeted absolute proteomics (QTAP) technique. In BBM fraction, the protein expression levels of bcrp, urat1, mate1, octl1, mrp4, mdr1a, and abca3 were 40.3, 22.2, 8.90, 4.85, 4.69, 3.22, and 0.976 fmol/μg protein, respectively. In BLM fraction, the protein expression levels of oat1, oat3, oct1, mrp6, and mrp1 were 10.6, 10.2, 4.59, 0.724, and 0.271 fmol/μg protein, respectively. The expression levels of abca2, abca4, abca5, abca12, abcb4, mrp5, abcc9, abcg1, abcg5, lat1, ntcp, pgt, oatp2b1, oatp1b2, oatp3a1, and oct3 were under the limit of quantification in both fractions. The quantitative transporter protein expression profiles at these membranes, as determined by QTAP analysis, should be helpful to understand the contributions of individual transporters to renal excretion of xenobiotics and endogenous compounds.
Distinct alterations in ATP-binding cassette transporter expression in liver, kidney, small intestine, and brain in adjuvant-induced arthritic rats
2014, Journal of Pharmaceutical Sciences
Citation Excerpt :
Therefore, changes in expression levels and functions of radixin could be possibly involved in the decrease of ABC transporters in membrane proteins of AA 7 d and AA 21 d. P-glycoprotein-mediated efflux transport has been shown to be involved in biliary excretion of substrates such as digoxin, doxorubicin, and vinblastine.40,41 Experiments in mdr1a (−/−) knockout mice have indicated that P-gp plays a role in cellular detoxification.42
Pathophysiological changes of infection or inflammation are associated with alterations in the production of numerous absorption, distribution, metabolism and excretion-related proteins. However, little information is available on the effects of inflammation on the expression levels and activities of ATP-binding cassette (ABC) transporters. We examined the effect of acute (on day 7) and chronic (on day 21) inflammation on the expression of ABC transporters in some major tissues in rat. Adjuvant-induced arthritis (AA) in rats was used as an animal model for inflammation. The mRNA levels of mdr1a and mdr1b encoding P-glycoprotein (P-gp) decreased significantly in livers of AA rats on day 21. Hepatic protein levels of P-gp, Mrp2, and Bcrp decreased significantly in membranes but not homogenates of AA rats after 7 days and after 21 days of treatment with adjuvant. Contrary to liver, protein levels of P-gp and Mrp2, but not Bcrp in kidney, increased significantly in membranes. The biliary excretion of rhodamine 123 was decreased in rats with chronic inflammation owing to decreases in efflux activities of P-gp. Our results showed that the expression of transporters in response to inflammation was organ dependent. In particular, hepatic and renal P-gp and Mrp2 exhibited opposite changes in membrane protein levels. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2556–2564, 2014
Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches
2021, Biopharmaceutics and Drug Disposition
Microdialysis in awake macaque monkeys for central nervous system pharmacokinetics
2018, Animal Models and Experimental Medicine
Organic anion transporting polypeptide 1a4 is responsible for the hepatic uptake of cardiac glycosides in mice
2018, Drug Metabolism and Disposition
The Role of Transporters in Drug Delivery and Excretion
2016, Drug Delivery: Principles and Applications: Second Edition

View all citing articles on Scopus

^†: Faculty of Pharmaceutical Sciences, Kanazawa University.

^‡: Present address: Hospital Pharmacy, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641.

^§: CREST, Japan Science and Technology Corporation.

View full text

Research ArticlesPhysiologically based pharmacokinetics of digoxin in mdr1a knockout mice

Abstract

Life Sci.

Eur. J. Cancer

Cell

J. Pharm. Sci.

Pharmacol. Ther.

J. Biol. Chem.

Gastroenterology

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

Biochem. Pharmacol.

Adv. Drug Deliv. Rev.

Adv. Drug Deliv. Rev.

Cellular localization of the multidrug resistance gene product in normal human tissues

Proc. Natl. Acad. Sci. U.S.A.

The three mouse multidrug resistance (mdr) genes are expressed in a tissue-specific manner in normal mouse tissues

Mol. Cell. Biol.

Research Articles
Physiologically based pharmacokinetics of digoxin in mdr1a knockout mice