Associate editor: H. BönischRole of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs
Introduction
There is increasing evidence that drug transport across biomembranes is subject to active and facilitated transport processes rather than simple passive diffusion, depending on physicochemical properties of the compound. Until recently it was commonly believed that physicochemical properties, such as size and lipophilicity, and metabolic processes are the major determinants of the bioavailability of most drugs. However, a number of foreign compounds exhibit intestinal absorption characteristics that do not follow simple diffusion processes but are actively transported through intestinal enterocytes into portal blood vessels or back into the intestinal lumen. Particularly the drug bioavailability at the site of action is influenced by active transport processes, a fact that is well known from drugs having a low bioavailability in the central nervous system due to active export processes at the blood–brain barrier. Therefore interindividual differences of plasma or liquor concentrations are due to varying expression levels or activity of both, metabolic enzymes and drug transporters in organ barriers or excretion organs (Fromm, 2004, Gerloff, 2004).
Drug transporters consist of uptake and efflux transporters, indicating intracellular or extracellular transport directions. It is believed that uptake carriers have been developed evolutionary to facilitate the cellular influx particularly of nutrients and vitamins and to reabsorb endogenous generated compounds such as glucose and other small carbohydrates, amino acids and small peptides, nucleosides, or bile acids in tubular ducts. Many of the uptake transporters use electrochemical gradients of ions such as Na+ or HCO3+ as a driving force enabling transports even against a concentration gradient. Therefore uptake transporters are complex transmembranal proteins with intra- and extracellular domains forming coupled symport or antiport ion channels. The main uptake carrier systems are organic anion transporters (OATP, solute carrier protein (SLC21A), organic cation transporters (OCT, SLC22A), concentrative nucleoside transporters (CNT, SLC28A), dipeptide transporters (PEPT, SLC15A), and monocarboxylate carriers (MCT, SLC28A) as excellently reviewed by Ho and Kim (2005).
Most efflux transporters belong to the ATP-binding cassette (ABC) superfamily of membrane proteins which may influence the intracellular concentration of numerous compounds in a variety of cells and tissues. These transporters play a major role as defense mechanism against penetration of xenobiotics or transmembrane transport of various endogenous compounds. The energy necessary for the substrate translocation across biomembranes is generated from the hydrolysis of ATP and intermediate phosphorylation of the transporter, enabling active transport of substrates against steep concentration gradients.
The ABC-transporter P-glycoprotein (P-gp, ABCB1) is doubtless the best characterized human drug transporter, but there is rapidly increasing understanding of the regulation and function of further members of the ABC-transporters related to the phenomenon of multidrug resistance (MDR) such as ABCC1 and ABCC2 (multidrug resistance-related proteins, MRP) and ABCG2 (breast cancer resistance protein, BCRP). In total, to-date there are at least 49 members of the ABC-transporter family, sub-dived into 7 subfamilies (http://nutrigene.4t.com/humanabc.htm). The proteins size spans 325 amino acids in ABCC13 up to 5058 amino acids in ABCA13. In general, most transporters have a size of 1500 AA. Most ABC-transporters are composed of 2 equal or unequal halves containing a membrane spanning domain and a nucleotide-binding fold (Borst & Elferink, 2002).
In the recent 6 years, numerous sequence variations in genes of the ABC transporter family have been identified, investigated for their frequency diversity in different ethnicities and particularly their functional impact on mRNA and protein expression, substrate specificity and bioavailability as well as the therapeutic outcome. This review focuses on the ABC transporters ABCB1, ABCC1, ABCC2, and ABCG2.
Section snippets
Function and expression
Initially, it was observed that ABC transporters like P-gp were overexpressed in tumor cells conferring the commonly known phenomenon of MDR against certain antineoplastic agents (Juranka et al., 1989). The gene encoding P-gp was therefore termed MDR gene 1 (formerly PGY1, now termed ABCB1).
Mice have 2 closely related homologues of ABCB1 (Abcb1a, Abcb1b). Mice homozygous for a dysfunctional Abcb1a gene but also double-knockout mice are viable and fertile but are sensitive to certain neurotoxins
ABCC1 (multidrug-resistance related protein 1)
The human ABCC1 protein was first identified in the doxorubicin-resistant small cell lung cancer cell line H69AR that did not overexpress P-gp (Cole et al., 1992). ABCC1 serves as a multispecific organic anion transporter for certain drugs such as folate-based antimetabolites, anthracyclines, plant alkaloids and antiandrogens. Moreover it is involved in the transport of GSH- and glutathione conjugates (Conseil et al., 2005) (Table 1). ABCC1 is expressed ubiquitous in the human body. In
Function and substrate specificity
The ATP-binding cassette (ABC) transporter MRP2, encoded by the ABCC2 gene is localized in the apical luminal membrane of polarized epithelial cells of several excretion organs like liver, intestine and kidney, but also in the blood–brain barrier and placenta (Konig et al., 1999, Young et al., 2003, Meyer zu Schwabedissen et al., 2005) (Table 2). ABCC2 has initially been designated as canalicular multispecific organic anion transporter (cMOAT). It actively exports anionic drug conjugates like
Function and substrate specificity
ABCG2, the so-called BCRP or mitoxantrone-resistant protein, is the second member of the G-family of ABC transporters (ABCG2) (Allikmets et al., 1998, Doyle et al., 1998). The ABCG2 gene is located at 4q22 and encodes a 72-kDa membrane protein composed of 655 amino acids (Bailey-Dell et al., 2001). The protein consists of only 1 ATP-binding region and 1 transmembrane domain and is referred to as a half-transporter, and its homodimerization may be necessary to transport substrates (Kage et al.,
Conclusion
In summary, the physiological consequences of ABCB1 genetic variants are still not well understood and the current figure of all findings is puzzling. The overall bioavailability of drugs seems to be only moderately influenced by the currently known ABCB1 SNP, at least as compared to variants of the CYP system (Ingelman-Sundberg, 2004, Cascorbi, 2005). It is interesting to note that among bioavailability studies performed in Caucasians often 3435T carriers presented higher plasma
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