In vitro Permeability and Drug Transporter Services
Cyprotex is a specialist provider of ADME and PK services and offer a range of in vitro permeability and uptake and efflux drug transporter assays. We offer both screening assays and full regulatory DDI and drug transporter packages according to FDA guidance and EMA guidance.
In vitro permeability assays
The permeability of drugs is an important factor in oral absorption, BBB permeation and transport of drugs into tissues and across cell membranes. The permeability of a drug across a membrane is dependent on the passive permeability as well as the susceptibility of the drug to undergo active efflux or uptake by drug transporter proteins.
Cyprotex offer a number of different models to study permeability including Caco-2 cells, MDCK-MDR1 cells and PAMPA as well as a panel of transporter assays which cover the key transporters recommended in the regulatory guidelines and those of emerging scientific interest. For more information on DDI studies, request our ADME guide or our DDI regulatory guidance booklet.
Drug transporter assays
Drug transporters exist in many tissues including, but not limited to, the intestinal epithelia, the hepatocytes and bile canaliculi, the kidney proximal tubules and the brain capillary endothelial cells.
The main transporters in these tissues are illustrated below.
Understanding whether your compound interacts with drug transporters (as a substrate or inhibitor) is an important stage in the drug development process. In vitro transporter interaction assays are used towards identifying if clinical drug-drug interaction studies are required.
The FDA guidance for industry (2020) and the European Medicines Agency (EMA) guideline on the investigation of drug interactions (adopted 2012) provides recommendations on the most clinically-relevant drug transporters for evaluation in the drug discovery and development process:
In addition to the main transporters above, the EMA and the International Transporter Consortium3,4 also recommends preferably evaluating:
In addition to these broadly recommended transporter studies, there are a number of other potentially clinically relevant transporters which may be important for particular drug-discovery programmes. These are discussed in the International Transporter Consortium (ITC) review whitepapers published in March 20105, July 20136 and November 20184.
Cyprotex provides an extensive portfolio of drug transporter services and provides support to in vitro drug interaction studies including data required for regulatory submission.
P-gp Interactions
P-gp (P-glycoprotein) is one of the most well-recognized efflux transporters. It is expressed in many tissues, including the intestine, brain, and kidney. P-gp inhibition has been shown to be responsible for several clinical drug-drug interactions. For example, clarithromycin can inhibit the transport of the P-gp substrate digoxin, resulting in an elevation of plasma levels and a decrease in renal clearance7.
Recommendations for studying P-gp inhibition and substrate identification are outlined in the FDA Guidance – In Vitro Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020)1 and in the EMA Guideline on the Investigation of Drug Interactions (Adopted 2012)2. Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our P-gp substrate identification and our P-gp inhibition services.
BCRP Interactions
BCRP (Breast Cancer Resistance Protein) is an efflux transporter expressed in several tissues such as the gastrointestinal tract, liver, brain endothelium, mammary tissue, testis, and placenta. BCRP is known to play a role in clinical drug-drug interactions. In addition, clinically relevant genetic polymorphisms have been shown to impact on the PK (e.g., irinotecan8, rosuvastatin9, sulfasalasine10 and topotecan11) and toxicity (e.g., gefitinib-induced diarrhea12) of marketed drugs. Recommendations for studying BCRP inhibition and substrate identification are outlined in the FDA Guidance for In Vitro Drug Interaction Studies (2020) and in the EMA Guideline on the Investigation of Drug Interactions (Adopted 2012)2. Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our BCRP substrate identification and our BCRP inhibition services.
OATP1B1 Interactions
Organic Anion Transporting Polypeptide 1B1 (OATP1B1) is expressed on the sinusoidal membrane of hepatocytes where it is responsible for the uptake of several marketed drugs including some statins13. There is evidence for clinical drug-drug interactions involving some statin drugs and cyclosporine which appear to be mediated, at least in part, by inhibition of OATP1B114,15.
The FDA guidance1 and the EMA guidance2 recommend investigating for potential OATP1B1 substrates and inhibitors due to the role of OATP1B1 in drug-drug interactions and the impact of genetic polymorphism of this transporter on therapy outcome and toxicity. According to the most recent regulatory guidance, it is only necessary to evaluate potential OATP1B1 substrates when hepatic clearance of the investigational drug is significant (e.g., hepatic elimination (hepatic or biliary clearance) is more than or equal to 25% of the total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our OATP1B1 substrate identification and our OATP1B1 inhibition services.
OATP1B3 Interactions
Organic Anion Transporting Polypeptide 1B3 (OATP1B3) is an uptake transporter expressed on the sinusoidal membrane of hepatocytes. It has a substrate specificity that overlaps somewhat with OATP1B116. Because of the prominent expression of these transporters on the sinusoidal membrane of hepatocytes, they represent a critical mechanism for uptake of drugs into the liver.
The FDA guidance1 and the EMA guidance2 recommend the evaluation of new chemical entities for their potential to act as substrates or inhibitors of OATP1B3 in vitro. It is only necessary to evaluate potential OATP1B3 substrates when hepatic clearance of the investigational drug is significant (e.g., hepatic elimination (hepatic or biliary clearance) is more than or equal to 25% of the total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our OATP1B3 substrate identification and our OATP1B3 inhibition services.
OAT1 Interactions
Organic Anion Transporter 1 (OAT1) is part of the SLC superfamily (SLC22A6). It is a transmembrane protein expressed predominantly at the basolateral membrane of proximal tubular cells of the kidneys and plays a central role in renal organic anion transport17. OAT1 is involved in the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys for subsequent exit across the apical membrane for excretion via the urine18. It has an essential role in the disposition of NSAIDs, antiviral drugs, diuretics, antitumor drugs and β-lactam antibiotics17.
The FDA guidance1 and the EMA guidance2 recommend investigating for potential OAT1 substrates and inhibitors due to the role of OAT1 in drug-drug interactions. It is only necessary to evaluate potential OAT1 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our OAT1 substrate identification and our OAT1 inhibition services.
OAT3 Interactions
Organic Anion Transporter 3 (OAT3) is part of the SLC superfamily (SLC22A8). Like OAT1, it is primarily expressed at the basolateral membrane of proximal tubular cells of the kidneys, facilitating its role is in the renal transport of organic anions17.
OAT3 exhibits a broader substrate specificity than OAT1, and accepts amphipathic and hydrophilic organic anions and some organic cations17. Drugs which are renally cleared and are actively secreted by OATs may be susceptible to increases in AUC as a result of OAT3 inhibition. Examples of these clinically relevant interactions include the interaction of probenecid with acyclovir, resulting in a 32% decline in renal clearance, a 40% increase in AUC, and an 18% increase in the terminal plasma half-life of acyclovir following probenecid administration19.
The FDA guidance1 and the EMA guidance2 recommend investigating for potential OAT3 substrates and inhibitors due to the role of OAT3 in drug-drug interactions. It is only necessary to evaluate potential OAT3 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our OAT3 substrate identification and our OAT3 inhibition services.
OCT2 Interactions
Organic Cation Transporter 2 (OCT2) is a member of the SLC family of transporters (SLC22A2). This transporter is expressed on the cells of the kidney proximal tubules where it is involved in the renal clearance of drug substrates20. Drug-drug interactions involving OCT2 may result in decreased renal clearance of the victim drug and a corresponding increase in exposure (e.g., cimetidine interaction with metformin21).
The FDA guidance1 and the EMA guidance2 recommend investigating for potential OCT2 substrates and inhibitors due to the role of OCT2 in drug-drug interactions. It is only necessary to evaluate potential OCT2 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our OCT2 substrate identification and our OCT2 inhibition services.
MATE1 Interactions
The human multidrug and toxin extrusion (MATE)-type transporter 1 (hMATE1, SLC47A1) is a key transporter for the secretion of organic cations. MATE1 can either act as an uptake or efflux transporter, depending on an oppositely directed proton gradient as the driving force. Therefore, extracellular alkalinization or intracellular acidification increases MATE1-mediated uptake in vitro, whereas extracellular acidification increases efflux by MATE122. Although MATE1 has been detected in several tissues, the main organ of expression appears to be the kidney. It is specifically located in the brush border (apical) membrane of the proximal and distal convoluted tubules23. Single nucleotide polymorphisms (SNPs) in the SLC47A1 gene have been implicated in altered metformin disposition in humans24.
Drug-drug interactions involving MATE1 may result in decreased renal clearance of the victim drug and a corresponding increase in exposure (e.g., cimetidine interaction with metformin21).
The FDA guidance1 and the EMA guidance2 recommend investigating for potential MATE1 substrates and inhibitors due to the role of MATE1 in drug-drug interactions. It is only necessary to evaluate potential MATE1 substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our MATE1 substrate identification and our MATE1 inhibition services.
MATE2-K Interactions
The human multidrug and toxin extrusion transporter 2-K (MATE2-K, SLC47A2) is a splicing variant of hMATE2. MATE2-K is an H+/organic cation antiporter which is located exclusively in the kidney on the brush border membrane of proximal tubules25. It plays an important role in extruding organic cations into the kidney26. Substrates of MATE2-K include metformin, cimetidine, TEA and procainamide, and there is considerable overlap in terms of substrate specificity with the MATE1 transporter27.
Drug-drug interactions involving MATE2-K may result in decreased renal clearance of the victim drug and a corresponding increase in exposure (e.g., cimetidine interaction with metformin21).
The FDA guidance1 and the EMA guidance2 recommend investigating for potential MATE2-K substrates and inhibitors due to the role of MATE2-K in drug-drug interactions. It is only necessary to evaluate potential MATE2-K substrates when renal active secretion of the investigational drug is significant (e.g., active secretion by the kidney is more than or equal to 25% of total clearance). Cyprotex follow the decision trees for identifying if an in vivo drug-drug interaction study is required using in vitro protocols recommended by the regulatory authorities.
Learn more about our MATE2-K substrate identification and our MATE2-K inhibition services.
BSEP Interactions
The Bile Salt Export Pump (BSEP) is a member of the ATP binding cassette family of transporters and is located on the canalicular membrane of hepatocytes. It is involved in transport of taurocholate and other cholate conjugates from hepatocytes to the bile and plays an important function in bile formation and bile flow28.
The European Medicines Agency2 and International Transporter Consortium3 suggest preferably evaluating the potential of new chemical entities to inhibit the BSEP transporter.
Learn more about our BSEP inhibition service.
OCT1 Interactions
Organic Cation Transporter 1 (OCT1) is a member of the SLC superfamily (SLC22A1) and is located on the basolateral membrane of hepatocytes and enterocytes29. It mediates facilitated transport of small (hydrophilic) organic cations30. The OCTs have been implicated in several clinically relevant drug interactions4.
The European Medicines Agency2 and International Transporter Consortium4 suggest that the investigation of new chemical entities for their ability to inhibit or be substrates of OCT1 in vitro could be considered.
Learn more about our OCT1 substrate identification and our OCT1 inhibition services.
MRP Interactions
MRP2 (multidrug resistance associated protein 2; ABCC2), MRP3 (ABCC3) and MRP4 (ABCC4) are ATP binding cassette (ABC) efflux transporters which are located on the brush border membrane of enterocytes (MRP2), the canalicular membrane (MRP2) or sinusoidal membrane (MRP3, MRP4) of hepatocytes, the brush border membrane of renal proximal tubule epithelial cells (MRP2, MRP4) and at the blood-brain barrier (MRP4)4. Consequently, these efflux transporters influence the absorption, distribution, metabolism and excretion of endobiotics (e.g. bile acids), drugs/and or metabolites within the body.
Learn more about our MRP substrate identification and our MRP inhibition services.
OATP1A2
Organic Anion Transporting Polypeptide 1A2 (OATP1A2) is a member of the SLC transporter family (SLCO1A2). Highest expression of OATP1A2 mRNA is observed in the brain, but it is also present in the liver, intestine, kidneys, lung and testes. OATP1A2 has a broad range of substrates including endogenous compounds such as bile acids, steroid hormones and their conjugates and thyroid hormones as well as various drugs such as fexofenadine, ouabain and methoxtrexate. The transport does exhibit pH dependency with methotrexate increasing 7‑fold at pH 5.0 compared with pH 7.431.
OATP1A2 is localized on the brush border membrane of enterocytes in the duodenum where it is thought to be involved in absorption and in the cholangiocytes of the liver where it is thought to be involved in reabsorption of xenobiotics excreted into the bile. It also plays a role in the renal transport and the blood brain barrier transport of xenobiotics. The transporter is thought to be important in breast cancer where mRNA expression in breast cancer tissue has been found to be almost 10‑fold higher than in healthy tissue, and it is believed that OATP1A2 may enhance hormone dependent breast cancer proliferation by facilitating estrone 3‑sulfate uptake in the cells31.
Learn more about our OATP1A2 substrate identification and our OATP1A2 inhibition services.
OATP2B1
Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is a member of the SLC transporter family (SLCO2B1). As well as being localized in the sinusoidal membrane of the liver where it is involved in uptake of drugs or endogenous substances and in the intestine where it plays a role in uptake and absorption, OATP2B1 is also expressed in the brain, lung, spleen, kidney, heart, placenta and ovaries32. OATP2B1 transport appears to be pH-dependent with an increased activity at acidic pH such as that observed in the weakly acidic intestinal32. The transporter is also expressed in a number of solid tumours. As the solid tumour microenvironment is acidic, it is thought OATP2B1 could also play a role in drug delivery to tumour cells33. Substrates of OATP2B1 include steroid conjugates, thyroid hormone and numerous drugs including statins32,34.
Learn more about our OATP2B1 substrate identification and our OATP2B1 inhibition services.
OAT2
Organic Anion Transporter 2 (OAT2) is a member of the SLC transporter family (SLC22A7). Expression of OAT2 is primarily expressed in the basolateral membrane of renal proximal tubule cells and is involved in active renal secretion of drugs or endogenous molecules35. OAT2 is also expressed in the liver and several other tissues in the body36. Substrates for OAT2 include acetyl salicylate, prostaglandin E2, dicarboxylates, glutamates, PAH as well as some anitvirals36. Of particular note is the transport of the endogenous substrate, cGMP, and it is thought therefore that OAT2 may be involved in modulation of intracellular signalling.
Learn more about our OAT2 substrate identification and our OAT2 inhibition services.
OAT4
OAT4 is a member of the SLC transporter family (SLC22A11). It is localized primarily in the syncytiotrophoblast cells of the placenta where it plays a role in regulating transport of hormones, drugs and toxins across the maternal-fetal barrier, and also in the apical membrane of renal proximal tubule cells where it is important for the reabsorption of organic anions, including sulfate conjugates36,37. Substrates of OAT4 include sulphated steroids, NSAIDs, anti-hypertensives, prostaglandins and uric acid36.
Learn more about our OAT4 substrate identification and our OAT4 inhibition services.
OCTN2
The organic cation / carnitine transporter 2 (OCTN2) is a member of the SLC transporter family (SLC22A5). It is expressed in the brush border membrane of the proximal renal tubule cells where it acts as a high affinity Na+/carnitine co-transporter and is responsible for the reabsorption of L‑carnitine and acetyl carnitine. These endogenous molecules are important in the transport of long chain fatty acids into mitochondria and subsequent energy production by β-oxidation38. OCTN2 is also expressed in skeletal muscle, placenta, heart, pancreas, liver, lung, intestine and brain tissue39. Transport can be bidirectional, with the direction dependent on the substrate. Other known substrates of OCTN2 include verapamil, cephaloridine and oxaliplatin39. Polymorphisms in OCTN2 have been associated with the clinical progression of intestinal inflammation in conditions such as Crohn's disease39.
Learn more about our OCTN2 substrate identification and our OCTN2 inhibition services.
PEPT1
Peptide transporter 1 (PEPT1) is a member of the SLC family of transporters (SLC15A1). It is a low affinity high capacity transporter which is proton dependent. PEPT1 is localized on the brush border membrane of the intestine and to a lesser extent on renal epithelial cells. It is also known to be present in certain cancer cells. The primary role of PEPT1 is the uptake of dipeptides, tripeptides or free amino acids in the small intestine following dietary protein digestion within the gastrointestinal tract40. Certain β-lactam antibiotics and anticancer agents are also substrates for PEPT1 in the intestine. Uptake by PEPT1 in the intestine is also a popular route for prodrug design for drug delivery. Prodrugs which have amino acids as promoieties have been designed to be substrates of PEPT1 to improve oral absorption and bioavailability. This has been successful in the case of anti-virals such as valacyclovir and valganciclovir41. There is also evidence of PEPT1 playing a role in the pathogenesis of intestinal inflammation42.
Learn more about our PEPT1 substrate identification and our PEPT1 inhibition services.
PEPT2
Peptide transporter 2 (PEPT2) is a member of the SLC transporter family (SLC15A2). It is a high affinity low capacity transporter. Like PEPT1, it is involved in the proton-coupled transport of dipeptides, tripeptides, amino acids and peptide-like drugs. PEPT2 is widely distributed in the body and is expressed in the kidney, central nervous system and lung as well as several other tissues43.
Learn more about our PEPT2 substrate identification and our PEPT2 inhibition services.
NTCP
The sodium/taurocholate cotransporting polypeptide (NTCP) is a member of the SLC transporter family (SLC10A1). NTCP is present on the sinusoidal membrane of hepatocytes where it is responsible for transporting bile salts into hepatocytes as part of the enterohepatic recirculation process. This is a process whereby bile is secreted by the hepatocytes, stored in the gall bladder and secreted into the intestine, from which many of its constituents are reabsorbed and recirculate via the portal vein back to the liver for re-uptake by NTCP. Although bile salts are the main substrate for NTCP, other substrates include estrone 3‑sulfate, bromosulfophthalein, dehydroepiandrosterone sulfate and thyroid hormones44. It has also been reported that NTCP contributes significantly to active hepatocyte uptake of statins45.
Learn more about our NTCP substrate identification and our NTCP inhibition services.
Preclinical species Oatp1b Interactions
Species differences in drug transporters with regard to their tissue distribution, expression levels and substrate specificity can be problematic for preclinical cross-species extrapolation of drug disposition (clearance) and DDI potential to human. The main hepatic uptake transporters expressed on the sinusoidal membrane of hepatocytes in preclinical species, which maybe rate-determining in the elimination of drugs, are rat Oatp1b2, dog Oatp1b4 and cynomolgus monkey Oatp1b1. Learn more about our Preclinical Oatp substrate identification and our Preclinical Oatp inhibition services.
References
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2 The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions (Adopted 2012)
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