Aliases: ABC20, CD243, CLCS, GP170, P-GP, PGY1
Gene name: ATP binding cassette subfamily B member 1 (ABCB1)
MDR1, more commonly referred to as P-gp or P-glycoprotein, is an efflux transporter that serves two major drug transport functions. Firstly, it restricts the distribution of its substrates into organs such as the brain, testes, placenta, and the GIT. Secondly, it eliminates its substrates from excretory organs, mediating both biliary and renal excretion, and occasionally direct gut secretion. Its role in modulating the tissue distribution of drugs is well established, particularly with respect to CNS exposure.
MDR1 has extremely wide substrate selectivity, preferentially transporting neutral or positively charged hydrophobic molecules, and appears to act synergistically with the enzyme CYP3A4 and with BCRP, another efflux transporter with which it shares many substrates and inhibitors. This synergistic interplay is considered particularly relevant in the gastrointestinal tract (GIT), where their combined actions modulate oral absorption of their drug substrates.
MDR1 is the most cited drug transporter in drug product labeling, and both the FDA and EMA guidances recommend testing of MDR1 interactions in vitro as a minimum requirement. The most important clinical substrate of MDR1 is digoxin, and drugs that are inhibitors of P-gp may require clinical assessment of their impact on digoxin PK. In the case of potential victim drugs whose ADME, and bioavailability in particular, is expected to be influenced by the action of MDR1, a clinical investigation may be appropriate with potent clinical MDR1 inhibitors as perpetrators. Because of the synergy between CYP3A4 and MDR1, contributions of both metabolism- and transporter-based mechanisms need to be clarified.
MDR1 comprises 1276–1280 amino acids with a molecular mass of approximately 170 kDa and a tandemly duplicated structure, with each half of the molecule containing six predicted highly hydrophobic transmembrane domains. It is ubiquitously expressed in the human body, with higher expression in the luminal membrane of barrier epithelia such as enterocytes or brain capillary endothelia, as well as in the apical membranes of excretory cells (e.g. hepatocytes and renal proximal tubule cells). MDR1 is also expressed at high levels on the surface of many transformed and tumor cell lines such as Caco-2.
Function, physiology, and clinically significant polymorphisms
In common with CYP3A4, MDR1 contains multiple substrate binding sites within the ligand binding domain [1, 2]. As a result, P-gp substrates include a broad range of clinically important and structurally diverse drugs (e.g. digoxin, quinidine, ritonavir, etoposide, and dexamethasone) , and endogenous substances (e.g. steroids and bilirubin). There is a significant overlap in the substrate specificities of CYP3A4 and MDR1, which are both highly expressed in the GIT and liver, and these proteins (along with BCRP) appear to act synergistically as a protective barrier in the bioavailability of orally dosed drugs. Many MDR1 inhibitors contain aromatic ring structures, a tertiary or secondary amino group, and have high lipophilicity. MDR1 inhibitors are typically either very high affinity substrates that bind non-competitively (i.e. not allowing other drugs to bind), or efficient inhibitors of ATP hydrolysis, either at the ATP binding site or by inhibiting protein kinase C (PKC), which is involved in ATP coupling to MDR1 . Transport is achieved by hydrolysis of approximately 2 moles of ATP per mole of drug transported.
MDR1 restricts the distribution of xenobiotics from the extracellular space into cells e.g. in the GIT or at the blood-brain barrier, or eliminates drugs/metabolites entering excretory cells from the blood side of the organ by transporting them into the bile, urine, or GIT.
In common with many drug metabolizing enzymes, MDR1 expression is known to be regulated by nuclear hormone receptors, including the Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR), and Farnesoid X Receptor (FXR), which act directly (PXR) or indirectly (FXR via PXR) in response to chronic treatment with xenobiotics such as rifampicin.
Of the numerous coding region SNPs reported at the ABCB1 locus, reviewed in an article by Wolking et al. , only three (e13/C1236T, e22/G2677T/A and e27/C3435T) have variable frequencies across populations and are associated with differences in drug response. Significantly increased exposure to irinotecan is associated with the 1236TT genotype and increased response to temozolomide, cyclosporine A and nelfinavir with the 1236CC genotype . Imatinib resistance was more frequent in Indian CML patients with the 1236TT genotype , while the 2677TT genotype protected against imatinib resistance in Egyptian CML patients . In in vitro studies, expression of e27/3435C correlated with increased efflux of the P-gp substrate rhodamine 123 , reduced efflux of nelfinavir, and had no effect on fexofenadine efflux . The G2677TT genotype was associated with lower plasma concentrations of fexofenadine, a higher risk of cyclosporine A failure in steroid-resistant ulcerative colitis, tacrolimus neurotoxicity, increased resistance to antiepileptic drugs, and increased response to cytarabine in AML patients. However, this SNP did not appear to affect plasma trough concentrations of ritonavir in HIV patients, rhodamine 123 efflux in peripheral blood lymphocytes, tacrolimus pharmacokinetics in renal transplant patients, or blood, semen and saliva concentrations of ritonavir or lopinavir in HIV patients. Interestingly, G2677T and C3435T are reported to protect Chinese but not Caucasian men from late-onset Parkinson’s disease [11-13].
Direct clinical evidence of the contribution of MDR1 inhibition or induction to drug-drug interactions (DDI) is limited partly because of cross-specificity of MDR1 substrates with the drug metabolizing enzyme CYP3A4. Due to its ubiquitous distribution, MDR1 may modulate absorption, distribution, metabolism and elimination (ADME) of its substrates, which complicates and often confounds clinical investigation of DDI potential. A comprehensive (although not exhaustive) list of in vitro as well as clinical substrates and inhibitors of MDR1 is curated and periodically updated by the FDA .
Digoxin is the most widely used drug for evaluation of MDR1 inhibition and induction, as it is eliminated essentially unchanged into urine in humans, has multiple DDI citations ascribed to MDR1, and is a widely prescribed cardiovascular drug. However, due to its narrow therapeutic index, it is not a particularly sensitive probe (<2-fold increases in exposure can lead to serious toxicity). Mibefradil was withdrawn as it increased the Cmax and AUC of digoxin to toxic levels. . Itraconazole increased plasma concentrations of digoxin, whilst decreasing its renal clearance . The AUC of digoxin significantly decreased when co-administered with the PXR activator rifampicin, likely due to increased intestinal expression of MDR1, which decreases absorption of digoxin from the GIT .
Phase I clinical trials with LY335979 (a potent MDR1 inhibitor) in patients with advanced malignancies reported neurotoxicity, cerebral dysfunction, hallucinations, and palinopsia when co-administered with doxorubicin . Similarly, inhibition of CYP isoforms and MDR1 by amiodarone, an antiarrhythmic drug, led to severe taxane toxicity in a breast cancer patient .
MDR1 contributes to the observed multi-drug resistance to many chemotherapeutic agents in patients. In clinical studies, MDR1 was induced 1.8-fold by chemotherapy, translating to a 3- to 4-fold greater incidence of treatment failure . Evaluation of breast cancers showed a strong correlation between taxol and doxorubicin resistance and MDR1 tumor expression .
Direct-acting oral coagulants such as dabigatran, apixaban, rivaroxaban, and edoxaban are all MDR1 substrates, and most are metabolised by CYP3A4. These drugs are frequently co-administered with cardiovascular drugs such as amiodarone or verapamil, both known inhibitors of MDR1. However, observed increases in plasma levels were moderate .
Overall, although there is a large body of evidence of the role of MDR1 in drug ADME, MDR1 inhibition appears to result in relatively modest DDIs, and is thought to be most impactful on the oral bioavailability of molecules. For most medicines, increased oral absorption is of limited clinical concern, as the change in exposure is small. Digoxin, however, is a special case, due to its narrow therapeutic window.
MDR1 is one of the most often cited transporters for DDI in drug product labels, and is of particular relevance in the safe use of the narrow therapeutic index drug digoxin. The FDA and EMA guidances recommend investigation of new chemical entity (NCE) interactions with P-gp as part of their development. Therefore, in vitro P-gp substrate and inhibition data are typically expected in regulatory submissions. Initial in vitro assessments are used to predict DDI potential, aiding the development of an MDR1 transporter-based clinical drug interaction strategy. Because of the apparent synergistic impact of MDR1 and CYP3A4 on the substrates of both proteins, an assessment of the relative contribution of both mechanisms, separately and/or together may be necessary, particularly where bioavailability is concerned.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|ubiquitous: intestinal enterocytes, kidney proximal tubule, hepatocyte canalicular membrane, brain endothelia, placenta, cornea||steroids, lipids, bilirubin, bile acids||calcein AM, digoxin, N-methyl-quinidine||Digoxin, dabigatran, loperamide, berberine, irinotecan, doxorubicin, vinblastine, paclitaxel, fexofenadine, seliciclib, quinidine, talinolol||
Cyclosporine, carvedilol, clarithromycin, amiodarone, dronedarone, itraconazole, ketoconazole, lapatinib, quinidine, reserpine, ritonavir, tacrolimus, tariquidar, elacridar, verapamil, valspodar (PSC833), zosuquidar (LY335979)
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