P-glycoprotein: Tissue Distribution, Substrates, and Functional Consequences of Genetic Variations Ingolf Cascorbi Contents 1 Introduction ............................................................................... 262 2 Tissue Distribution ........................................................................ 263 2.1 Intestine ............................................................................. 263 2.2 Liver ................................................................................ 263 2.3 Kidney .............................................................................. 264 2.4 Blood–Brain Barrier ................................................................ 264 2.5 Placenta ............................................................................. 264 2.6 Lymphocytes ........................................................................ 265 3 Substrates ................................................................................. 265 4 ABCB1 Genetic Polymorphisms .......................................................... 266 4.1 Functional Consequences of Genetic Variations .................................... 266 4.2 Association to Drug Bioavailability ................................................ 267 5 Conclusion ................................................................................ 275 References .................................................................................... 275 Abstract P-glycoprotein (ABCB1, MDR1) belongs to the ABC transporter family transporting a wide range of drugs and xenobiotics from intra- to extracellular at many biological interfaces such as the intestine, liver, blood–brain barrier, and kidney. The ABCB1 gene is highly polymorphic. Starting with the observation of lower duodenal protein expression and elevated digoxin bioavailability in relation to the 3435C>T single nucleotide polymorphism, hundreds of pharmacokinetic and outcome studies have been performed, mostly genotyping 1236C>T, 2677G>T/A, and 3435C>T. Though some studies pointed out that intracellular concentrations of anticancer drugs, for example, within lymphocytes, might be affected by ABCB1 variants resulting in differential outcome, current knowledge of the functional significance genetic variants of ABC membrane transporters does not allow selec- tion of a particular SNP to predict an individual’s pharmacokinetics. I. Cascorbi Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Bldg. 30, 24105 Kiel, Germany e-mail: cascorbi@pharmakologie.uni-kiel.de M.F. Fromm and R.B. Kim (eds.), Drug Transporters, Handbook of Experimental Pharmacology 201, DOI 10.1007/978-3-642-14541-4_6, # Springer-Verlag Berlin Heidelberg 2011 261