Transporter-mediated drug-drug interactions Flashcards
Transporter-mediated drug-drug interactions (tDDIs) may occur at:
- Both uptake and efflux transporters (cyclosporine)
Multiple organs – rosuvastatin - liver (OATP1B1) and intestine (BCRP) - Transporters and enzyme (gemfibrozil glucuronide – inhibits OATP1B1 and CYP2C8)
Impact on systemic and tissue drug concentration (safety and efficacy)
How many membrane transporters?
> 400 membrane transporters identified so far
Two major super families of transporters in human genome:
- ATP-binding cassette (ABC)
- Solute carrier (SLC)
Most relevant transporters expressed in:
- Epithelia of the intestine, liver and kidney
- Endothelium of the blood–brain barrier
OATP - Organic Anion Transporting Polypeptide – OATP1B1 (MAJOR) and OATP1B3 located:
on sinusoidal membrane of hepatocytes
OATP1B1 mediates uptake of :
Therapeutic drugs into hepatocytes - statins, repaglinide, valsartan (anionic substrates)
Endogenous compounds - bile acids, bilirubin, thyroxine hormone
OATP1B3 – similar in sequence to OATP1B1
- Overlap in substrates with OATP1B1
- Active uptake of glutathione into hepatocytes
Clinical relevance of OATP1B1:
Active uptake of statins (acid form!) via OATP1B1:
- Higher liver exposure compared to plasma
- Important for therapeutic effect of statins as this is where statins actually work
Expression and activity of OATP1B1 varies between individuals / ethnicities:
SLCO1B1 c.521T>C most relevant SNP
521 CC - decreased OATP1B1 activity, increased risk of myopathy when taking statins
Co-administration of OATP1B1 inhibitor:
Decreased active uptake of victim drug into hepatocytes
Increases plasma concentrations of the ‘victim’ drug and risk of adverse reactions
Clinical example of OATP1B1 DDI – cyclosporine interaction with rosuvastatin in transplant patients. Mechanism of DDI:
- Cyclosporine inhibits hepatic uptake of statins by OATP1B1 transporter so less gets taken up into hepatocycte and now more is in the systemic circulation
Likelihood of co-medication – very HIGH!
Cardiovascular diseases major problem in long-term transplant recipients
Clinical example of OATP1B1 DDI – cyclosporine interaction with rosuvastatin in transplant patients. Consequences:
- Increased plasma concentrations of rosuvastatin
- Safety concern- Impact on drug labelling and recommended initial dose of rosuvastatin
- Similar interaction reported with other statins (atorvastatin, simvastatin)
What is the role of efflux transporters in clinically relevant DDIs?
Multiple roles of P-glycoprotein in drug disposition1,2
- Intestinal absorption and bioavailability
- Limits entry of drugs into the CNS
- Biliary and renal excretion of drugs
Small number of clinically relevant DDIs can be attributed solely to inhibition of P-gp:
- Overlap in substrates with CYP3A4 (loperamide, vinblastin etc)
- Dual substrates - inhibition of CYP3A4 often the major cause of DDI!
Most relevant P-gp DDIs are with digoxin as a substrate:
- Safety concerns due to its narrow therapeutic index
- Recommended probe by FDA for assessing P-gp inhibition
Dabigatran etexilate or fexofenadine (EMA)
Examples of transporter food-drug interaction: Curcumin
- Curcumin (turmeric) inhibits intestinal efflux of sulfasalazine via BCRP.
- Sulfasalazine - anti-inflammatory drug used to treat ulcerative colitis and Crohn’s disease
Low permeability, low solubility and efficient intestinal BCRP efflux – drug restricted largely to the GI tract - What is the consequence of inhibition of BCRP? Increased absorption and decreases its exposure to intestinal bacteria (bad as it treats there intestinal disorders)
Examples of transporter food-drug interaction: Apple juice
- Apple juice inhibits intestinal uptake via OATP2B1
Reduced plasma concentrations of aliskiren and fexofenadine when taken with apple juice instead of water - Complex inhibition interaction via multiple components
Evaluation of transporter-mediated PK and DDIs in drug development:
- Drugs tested for their ability to inhibit major transporters
OATP1B1, OATP1B3, P-gp, BCRP, OATs, OCT2, MATE
Decision trees to decide on whether to do a clinical transporter DDI study - Conducting clinical studies to test potential interaction on every transporter (in patient population) is logistically impossible!
- -> Increased use of modelling and simulation (PBPK models)
Recent examples of mechanistic modelling of transporter-mediated disposition:
- Transporter-mediated DDIs (simeprevir)
- PK in organ impairment (hepatic impairment – obeticholic acid)
- Extrapolation across ethnic groups (letermovir)
Other in vivo methods to investigate risk of transporter DDIs:
- Clinical studies with cocktails of drug transporter probes (microdosed)
- Endogenous biomarkers
3. Use of preclinical species Cynomolgus monkey (Shen et al., 2013, Chu et al 2015)
- Positron emission tomography (PET) imaging
Endogenous biomarkers of hepatic and renal transporter:
Many endogenous molecules are substrates of drug transporters coproporhyrin I, bile acids, fatty acids – OATP1B1
Can change in AUC of a biomarker reflect changes in drug’s AUC in DDI? Good as can be done very early stages
Required properties of biomarkers:
- Selectivity
- Sensitivity – ability to detect weak/moderate transporter inhibitors
Rate of biomarker formation and elimination:
Effect of disease, diet, age, circadian rhythm?
Why is CPI the most promising endogenous biomarker for OATP1B?
- CPI is a by-product of haeme synthesis
- Reported interactions with rifampicin and other OAT1B inhibitors
- Increased urinary excretion of CPI in Rotor’s syndrome
- Metabolically stable, excreted in the bile and urine
- Stable inter-occasion baseline and <25% inter-individual variability in subjects with wild type OATP1B1
PET imaging to study tissue distribution and transporter DDIs:
- Allows investigation of changes in tissue PK
- Ideal PET tracer:
Transporter specific
Metabolically stable
Amenable to radiolabelling (11C) - PET tracer administered as a microdose (1-10 µg) in DDI studies
Summary:
- Increased recognition of clinical relevance of tDDIs
Mostly associated with OATP1B1, P-gp
DDIs with renal transporters (see Renal Elimination lecture) - Evaluation of changes in drug tissue concentration as a result of tDDI is challenging
Role of PBPK modelling and PET imagining - Prospective assessment of DDI risk for drugs that are substrates or inhibitors of multiple transporters and/or enzymes is complex
