NORMAL VIABILITY AND ALTERED PHARMACOKINETICS IN MICE LACKING MDR1-TYPE (DRUG-TRANSPORTING) P-GLYCOPROTEINS

The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to c ancer cells by active extrusion of a wide range of drugs from the cell . To study their physiological roles, we have generated mice genetical ly deficient in the mdr1b gene [mdr1b (-/-) mice] and in both the mdr1 a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of funct ions speculatively attributed to the mdr1-type P-gps, we found no phys iological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunologica l parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdr1b P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, althou gh the protein did reduce drug accumulation in the adrenal gland and o varies. Pharmacologically, mdr1a/1b (-/-) mice behaved similarly to th e previously analyzed mdr1a (-/-) mice, displaying, for instance, incr eased brain penetration and reduced elimination of digoxin. However, b oth mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine fr om hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytot oxic anticancer drugs. This, and the normal viability of mdr1a/1b (-/- ) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) mice should provide a useful m odel system to further test the pharmacological roles of the drug-tran sporting P-gps and to analyze the specificity and effectivity of P-gp- blocking drugs.