In humans there is only a single drug-transporting Pgp (MDR1 Pgp), whereas two Pgps are present in mice: mdr1a (also called mdr3) Pgp and mdr1b (also called mdr1) Pgp (13). Presumably, the two Pgps in mice jointly fulfill the same function as the single MDR1 Pgp in man (14). The distribution of mdr1a Pgp and mdr1b Pgp in mice is organ specific (15), with mdr1a being the exclusive Pgp at the blood-brain barrier (BBB), in the intestinal mucosa, and at the blood-testis barrier, whereas mdr1b is the only Pgp detected at the blood-placenta and blood-ovary barriers, and in the cortex of the adrenal glands. Both Pgps are expressed in the kidney and the liver. Three strains of knockout mice [mdrla (— / —) mice, mdrlb (— /—) mice, mdrla/lb (—/ —) mice] were generated by homozygous disruption of the mdrla or mdrlb gene or both. Under laboratory conditions, all three strains of knockout mice showed normal life expectancy, were fertile, and yielded no abnormal histological or laboratory chemistry findings (16, 17). Direct intestinal Pgp-mediated secretion of transported substrates from systemic circulation into the intestinal lumen was demonstrated in pharmacokinetic investigations (e.g., with digoxin, paclitaxel) (18, 19). In other tissues (adrenals, testes, ovaries), in which Pgp is expressed under physiological conditions, elevated concentrations of Pgp substrates in mdr1a Pgp- or mdr1b Pgp-deficient knockout mice were interpreted as indicative of defective organ protection (16, 17, 20).
The following discussion focuses on the function of Pgp in the apical membrane of brain capillary endothelial cells at the BBB with a particular focus on the significance of the loss of functional Pgp for drug transport to the central nervous system (CNS).
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