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Pharmacological insights from P-glycoprotein knockout mice
1Division of Experimental Therapy, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Abstract:
The mdr1-type P-glycoproteins can confer multidrug resistance to tumor cells by actively pumping a wide variety of drugs from the cell. To counteract this drug resistance, P-glycocoprotein-blocking agents are currently administered to patients during chemotherapy. However, this may also affect the normal physiological function(s) of the mdr1-type P-glycocoproteins. In order to establish these functions, we have generated mice with a genetic deficiency in both of their mdr1-type P-glycocoprotein genes. Our results indicate the mdr1-type P-glycocoproteins are not essential for basic physiological functions. However, mice without mdr1-type P-glycocoproteins display drastic alterations in the pharmacological handling of drugs, demonstrating an important role for mdr1-type P-glycocoprotein in the blood-brain barrier, where it prevents the accumulation of many drugs in the brain. Moreover, we found that intestinal P-glycocoprotein has a prominent role in the extrusion of several drugs from the blood into the intestinal lumen, and in preventing drugs in the intestinal lumen from (re-)entering the bloodstream. The latter property can have important implications for the oral bioavailability of many drugs. Our results indicate that effective P-glycocoprotein-blocking agents should be used with caution, given the potentially extensive pharmacokinetic effects of treatment with these compounds.
Insights
Mice lacking mdr1-type P-glycoproteins show altered drug processing, highlighting their role in the blood-brain barrier and gut. These findings suggest caution when using P-glycoprotein blockers during chemotherapy.
Area of Science:
- Pharmacology
- Molecular Biology
- Genetics
Background:
- Mdr1-type P-glycoproteins in tumor cells cause multidrug resistance by exporting drugs.
- P-glycoprotein blockers are used in chemotherapy but may disrupt normal physiological functions.
- The precise physiological roles of mdr1-type P-glycoproteins remain unclear.
Purpose of the Study:
- To investigate the physiological functions of mdr1-type P-glycoproteins.
- To determine the impact of genetic deficiency in mdr1-type P-glycoproteins on drug handling.
Main Methods:
- Generation of genetically deficient mice lacking both mdr1-type P-glycoprotein genes.
- Assessment of physiological functions and drug pharmacokinetic profiles in these mice.
Main Results:
- Mice deficient in mdr1-type P-glycoproteins are viable and do not exhibit essential physiological deficits.
- Significant alterations in drug pharmacokinetics were observed, particularly in drug distribution to the brain.
- Mdr1-type P-glycoproteins play a crucial role in limiting drug entry into the brain via the blood-brain barrier.
- Intestinal P-glycoprotein was found to be vital for drug extrusion into the intestinal lumen and preventing reabsorption.
Conclusions:
- Mdr1-type P-glycoproteins are not essential for basic physiological functions.
- These proteins are critical for drug transport at the blood-brain barrier and in the intestine.
- The use of P-glycoprotein-blocking agents warrants caution due to potential pharmacokinetic alterations and impacts on oral drug bioavailability.