Mdrla

Smit, J. W., et al. Contribution of the murine mdrla P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdrla gene disruption. Hepatology 1998, 27, 1056-1063. 

B., Meijer, D. K., Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdrla and mdrlb genes have been disrupted, Br. J. Pharmacol. 1998, 124, 416-424. 

C. A. A. M., van der Valk, M. A., RobanusMandaag, E. C., Borst, P., Disruption of the mouse mdrla P-glycoprotein gene leads to a deficiency in the blood brain barrier and to increased sensitivity to drugs, Cell 1994, 77, 491-502. 

Schinkel, A. H., Wagenaar, E., van Deemter, L., Mol, C. A., Borst, P., Absence of the mdrla P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamefhasone, digoxin, and cyclosporin A, J. Clin. Invest. 1995, 96, 1698-1705. 

Dagenais C, Rousselle C, Pollack GM, Scherrmann JM. Development of an in situ mouse brain perfusion model and its application to mdrla P-glycoprotein-defi-cient mice. J Cereb Blood Flow Metab 2000 20 381-386. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Saito, T., Zhang, Z. J., Ohtsubo, T., et al. (2001) Homozygous disruption of the mdrla P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs. Acta Otolaryngol. 121, 735-742. 

Uhr M, Grauer MT (2003) abcblab P-glycoprotein is involved in the uptake of citalopram and trimipramine into the brain of mice. J Psychiatr Res 37 179-185 Uhr M, Sleekier T, Yassouridis A, Holsboer F (2000) Penetration of amitriptyhne, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Nemopsychopharmacology 22 380-387... 

Stephens, R.H., et al. 2002. Resolution of P-glycoprotein and non-P-glycoprotein effects on drug permeability using intestinal tissues from mdrla (-/-) mice. Br J Pharmacol 135 2038. 

Rodent mdrla/mdrlb /lipid soluble) plexus apical membrane... 

Uhr, M., et al. 2000. Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdrla P-glycoprotein gene disruption. Neuropsychopharmacology 22 380. 

Kawahara M, Sakata A, Miyashita T, Tamai I, Tsuji A. Physiologically based pharmacokinetics of digoxin in mdrla knockout mice. J Pharm Sci 1999 88 1281-1287. 

Panwala CM, Jones JC, Viney JL. A novel model of inflammatory bowel disease mice deficient for the multiple drug resistance gene, mdrla, spontaneously develop colitis. J Immunol 1998 161 5733-5744. 

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). 

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