title: P-glycoprotein activity and biological response.
abstract: P-glycoprotein (P-gp) is a transmembrane drug efflux pump encoded by the MDR-1 gene in humans. Most likely P-gp protects organs against endogenous and exogenous toxins by extruding toxic compounds such as chemotherapeutics and other drugs. Many drugs are substrates for P-gp. Since P-gp is also expressed in the blood-brain barrier, P-gp substrates reach lower concentrations in the brain than in P-gp-negative tissues. Failure of response to chemotherapy of malignancies can be due to intrinsic or acquired drug resistance. Many tumors are multidrug resistant (MDR); resistant to several structurally unrelated chemotherapeutic agents. Several mechanisms are involved in MDR of which P-gp is studied most extensively. P-gp extrudes drugs out of tumor cells resulting in decreased intracellular drug concentrations, leading to the MDR phenotype. Furthermore, the MDR-1 gene exhibits several single nucleotide polymorphisms, some of which result in different transport capabilities. P-gp functionality and the effect of P-gp modulation on the pharmacokinetics of novel and established drugs can be studied in vivo by positron emission tomography (PET) using carbon-11 and fluorine-18-labeled P-gp substrates and modulators. PET may demonstrate the consequences of genetic differences on tissue pharmacokinetics. Inhibitors such as calcium-channel blockers (verapamil), cyclosporin A, ONT-093, and XR9576 can modulate the P-gp functionality. With PET the effect of P-gp modulation on the bioavailability of drugs can be investigated in humans in vivo. PET also allows the measurement of the efficacy of newly developed P-gp modulators.
authors.affiliation: Groningen University Hospital, PO Box 30.001, 9700 RB Groningen, The Netherlands. w.vaalburg@pet.umcg.nl
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
authors.forename: N H
authors.initials: NH
authors.lastname: Hendrikse
authors.forename: P H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: J
authors.initials: J
authors.lastname: Bart
authors.forename: A
authors.initials: A
authors.lastname: van Waarde
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D011110:Polymorphism, Genetic; D049268:Positron-Emission Tomography; D011869:Radioligand Assay
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1