MDRla/lb mice

Fexofenadine is mainly excreted into the bile and urine without metabolism. Many transporters are involved in the pharmacokinetics of fexofenadine. OATP1A2 (212), OATP2B1 (299), OATP1B3 (300), OAT3 (301), and P-gp (212) have been suggested to accept fexofenadine as substrate. On the basis of in vivo study using Mdrla and Mdrla/lb(-/-) mice, it has been shown that P-gp limits intestinal absorption and brain penetration of fexofenadine, but makes only a limited contribution to the biliary and urinary excretion (212,302). Furthermore, inhibition of P-gp in the intestine allowed detection of saturable uptake of fexofenadine and inhibition by Oatp inhibitor in rats (88). 

In conclusion, Pgp is involved in the regulation of various physiological processes. Furthermore, the fact that mdrla(-/—) and mdrla/lb(—/—) mice appear normal suggests that Pgp does not have an essential role in life, although it should be taken into account that due to the knockout of mdrla and mdrlb genes, Pgp function may be compensated by other transporters. 

Important evidence for the role of Pgp at the BBB was obtained from experiments with mdrla(-/-) and mdrla/lb(-/-) mice. The significantly higher accumulation of several drags in the brains of these mice in comparison to most other tissues and plasma demonstrated its important role (62). In addition, increased accumulation of these drags in various tissues can affect their pharmacodynamics (63). This is best illustrated by centrally acting drags. Morphine is often used as a narcotic analgesic for the treatment of pain. It acts at the opioid receptors within the CNS at both the spinal and supraspinal levels. In vitro and in vivo studies have... 

Figure 18.2. Effects of GF120918 on the plasma concentration and biliary excretion of topo-tecan in mice. Mdrla/lb (-/-) (a) or wild-type (b) mice were given an oral dose of GF120918 (50 mg/kg) or vehicle 15 minutes before an oral dose of topotecan (1 mg/kg). (c) Mdrla/lb (-/-) mice were given an i.v. dose of topotecan in combination of an oral GF120918 or vehicle. (d) Cumulative biliary excretion of topotecan in mdrla/lb (-/-) mice treated in the same way as (c). Results are the means SD (n 3). (Reproduced with permission from ref. 16).

Liu, J., Y. Liu, D.A. Powell, M.P. Waalkes and C.D. Klaassen. Multidrug-resistance mdrla/lb double knockout mice are more sensitive than wild type mice to acute arsenic toxicity, with higher arsenic accumulation in tissues. Toxicology 170 55-62, 2002. 

To further evaluate the potential utility of the Ga-complex as an in vivo marker of Pgp-mediated transport activity, the complexes were injected in wild-type and mdrla/lb (-/-) knoekout mice to study the drug transport across the BBB. As previously mentioned, Pgp is expressed in the luminal surfaces of brain endothelial cells preventing the entry of amphipathic compounds into the central nervous system. Therefore, the mdrla/lb (-/-) knockout mice offer an interesting model to evaluate the applicability of radiotracers for in vivo transport activity of Pgp. At 5 min after injection, the brain uptake of Ga-complex in Pgp-knockout miee was 10-fold higher compared with that in the wild-type mice. As the cerebral blood flow did not differ significantly between the wild-type and the knockout mice, differences on initial brain uptake and retention of Ga-complex were not attributed to changes in cerebral perfusion. 

Johnson DR, Finch RA, Lin ZP, Zeiss CJ, Sartorelli AC (2001) The pharmacological phenotype of combined multidrug-resistance mdrla/lb- and mrpl-deficient mice Cancer Res 61 1469-1476. 

Smit, J.W., A.H. Schinkel, B. Weert and D.K. Meijer. Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdrla and mdr lb genes have been disrupted. Br. J. Pharmacol. 124 416-424, 1998. 

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