Drug Transporters 2024 Student Version PDF

Drug Transporters Zackery P. Bulman, Pharm.D. [email protected] Assistant Professor Department of Pharmacy Practice College of Pharmacy University of Illinois at Chicago Learning Objectives 1) Describe the importance...

Drug Transporters Zackery P. Bulman, Pharm.D. [email protected] Assistant Professor Department of Pharmacy Practice College of Pharmacy University of Illinois at Chicago Learning Objectives 1) Describe the importance of drug transporters in drug disposition. 2) Describe the role of drug transporters in managing passage of compounds through the blood brain barrier. 3) Explain the importance of P-glycoprotein, PEPT1, and OATP1B1 to the disposition of various drug substrates. 4) Understand the importance of porin channels and efflux pumps in bacteria for the activity of antibiotics.  Introduction to Drug Transporters Drug transport = movement through membranes Movement can occur through cells (transcellular) or between cells (paracellular) Some drugs move through membranes unaided due to favorable physiochemical properties (lipophilic) Transporter Passive Transcellular Drug transport for many drugs is facilitated by transporters across membranes Facilitated Transcellular Transporters alter pharmacokinetics, safety, and efficacy of drugs Rowland and Tozer Fig. 4-2  Introduction to Drug Transporters Types of transporters Active Influx Passive Influx Passive Efflux Active Transporters: ATP dependent and against the concentration gradient (ex. ABC transporters) Passive Transporters: facilitates transport in ATP the direction of the concentration gradient (ie. no effect at equilibrium) Influx Transporter: into the cell Efflux Transporter: out of the cell Passive Efflux Rowland and Tozer Fig. 4-7  Introduction to Drug Transporters Substrate Substrate + Drug Transporter Substrate Alone Inhibitor Substrate = can pass through Substrate Substrate Inhibitor transporter Drug Transporter Inhibitor Inhibitor = can inhibit transporter X and block substrates Can cause drug-drug interactions Rowland and Tozer Fig. 4-7  Blood Brain Barrier Tight Junctions BBB separates the brain and extracellular fluid in the CNS from circulating blood Consists of endothelial cells and tight A. Passive Diffusion junctions Tight Junctions=No paracellular transport For drugs with favorable physiochemical properties (small, lipophilic, no charge), passage through BBB can overcome efflux (Figure A) Efflux Rowland and Tozer Fig. 4-9  Blood Brain Barrier BBB separates the brain and extracellular fluid in the CNS from circulating blood Consists of endothelial cells and tight Passive Diffusion B. junctions Tight Junctions=No paracellular transport For drugs with less favorable physiochemical properties, efflux keeps CNS concentrations of drug low (Figure B) Efflux Rowland and Tozer Fig. 4-9 Drug Transporter Examples There are hundreds of transporters in humans but only a few have well characterized effects on drug pharmacokinetics and/or drug-drug interactions P-glycoprotein OATP1B1 PEPT1 Giacomini et al. Nature Reviews: Drug Discovery. 2010. Drug Transporter Examples There are hundreds of transporters in humans but only a few have well characterized effects on drug pharmacokinetics and/or drug-drug interactions P-glycoprotein OATP1B1 PEPT1 Giacomini et al. Nature Reviews: Drug Discovery. 2010. P-glycoprotein P-glycoprotein (P-gp): permeability glycoprotein is an efflux pump that works to eliminate drugs from the cell Ubiquitously expressed (primary sites include intestine, brain, liver, and kidney) Also called the multiple drug-resistant receptor (MDR1) P-gp will efflux drugs out of cells thus causing resistance to those drugs  P-glycoprotein Active transporter (ABC family) Important for limiting drug entry through BBB Facilitates biliary and urinary excretion of drugs TRANSPORTER SUBSTRATES INHIBITORS LOCATION Cyclosporine, Digoxin, loperamide, quinidine, Intestinal epithelia, irinotecan, doxorubicin, verapamil, P-gp kidney, hepatocytes, vinblastine, paclitaxel, clarithromycin, brain fexofenadine amitriptyline, ritonavir P-glycoprotein and Intestinal Epithelia PO IV Paclitaxel Example P-gp reduces paclitaxel concentrations following PO No P-gp in the dosing by limiting uptake intestine through intestine P-gp reduces paclitaxel With P-gp concentrations following IV in the dosing by secretion into intestine intestinal lumen Sparreboom et al. PNAS. 1997.  P-glycoprotein and the Kidney Digoxin Digoxin P-gp in the proximal tubule of the + kidney allows for secretion of Cyclosporine Renal Tubular Secretion drug into the urine Digoxin Example: Digoxin is renally effluxed via P-gp Co-administration of digoxin with a P-gp inhibitor (ie. cyclosporine) reduces the tubular secretion = **Note the y-axis increased digoxin plasma levels is renal tubular secretion, not drug Drug-Drug Interaction concentration Okamura et al. J Pharmacol and Experimental Therapeutics. 1993. P-glycoprotein and the Kidney Clinical Pharmacology. Drug Interaction Report.  P-glycoprotein and Ritonavir Ritonavir is co-administered with other drugs as a ‘PK Booster’ Examples: Nirmatrelvir/Ritonavir (Paxlovid) and Lopinavir/Ritonavir Ritonavir is a strong cytochrome P450 inhibitor (CYP3A4) AND a Ex. Drug-Drug Interaction between ritonavir and digoxin P-glycoprotein inhibitor Ritonavir is typically administered for its ability to inhibit CYP3A4 Ritonavir Inhibition of P-glycoprotein is an Blood Urine unintended result that can lead to Digoxin drug-drug interactions P-gp Kidney proximal tubules P-glycoprotein and Hepatocytes P-gp substrates may be returned to the intestines via biliary excretion due to the presence of P-gp in the hepatocytes. Rowland and Towzer, Fig. 7-5. Giacomini et al. Nature Reviews: Drug Discovery. 2010. P-glycoprotein and the BBB P-gp Inhibitor NIH/NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES  P-glycoprotein and the BBB Loperamide Without Loperamide With P-gp P-gp Inhibitor Inhibitor Loperamide With P-gp Inhibitor Radiolabeled Loperamide Conc. In Brain Loperamide Without P-gp Inhibitor Loperamide Example P-gp inhibitors given with loperamide increase loperamide concentrations in the brain Liow et al. J Nucl Med. 2009. Practice Question 1) Which of the following would you expect to occur when you co-administer paclitaxel and cyclosporine compared to administering paclitaxel alone? Select all that apply. A. Decreased paclitaxel concentrations in the brain B. Decreased serum paclitaxel concentrations C. Decreased biliary excretion of paclitaxel D. Decreased renal excretion of paclitaxel E. None of the above Drug Transporter Examples There are hundreds of transporters in humans but only a few have well characterized effects on drug pharmacokinetics and/or drug-drug interactions P-glycoprotein OATP1B1 PEPT1 Giacomini et al. Nature Reviews: Drug Discovery. 2010. OATP1B1 Organic Anion Transporting Polypeptide (OATP) Protein encoded by SLCO1B1 Uptake transporter expressed on sinusoidal side of hepatocytes Transports endogenous bilirubin, bile acids from blood into hepatocytes Also transports exogenous compounds (drugs) TRANSPORTER SUBSTRATES INHIBITORS LOCATION Statins, repaglinide, Saquinavir, ritonavir, valsartan, olmesartan, OATP1B1 lopinavir, rifampicin, Hepatocytes bilirubin glucuronide, cyclosporine, gemfibrozil bilirubin, bile acids OATP1B1 and Statins Statins Statins inhibit HMG-CoA reductase in the liver = lower cholesterol Statins are substrates of OATP1B1 transporters Statins are first line therapy for hypercholesterolemia and widely used Statin use in 40+ year old people increased from 17.9% in 2002-03 to 27.8% in 2012-13 Giacomini et al. Nature Reviews: Drug Discovery. 2010. Salami et al. JAMA Cardiology. 2017. OATP1B1 and Statins Less statin into More statin Higher risk of Inhibition of the remains in the side effects OATP1B1 hepatocytes blood (myopathy) Schneck et al. Clinical Pharmacology and Therapeutics. 2004. OATP1B1 Genetic Variation There are various single nucleotide polymorphisms (SNPs) in the OATP1B1 transporter gene that cause variations in structure Some SNPs lead to decreased transport of statins, thus causing increased side effect risk (myopathy) V174A is common SNP that leads to nonfunctional OATP1B1 Predicted variations in OATP1B1 structure (each red highlighted amino acid position has been found to vary within the population) Niemi et al. Pharmacological Reviews. 2011. Practice Question 2) Genetic polymorphisms of OATP1B1 that are associated with nonfunctional transporter activity would lead to: A. Increased hepatotoxicity of statins B. Decreased efficacy of statins C. Decreased myopathy of statins D. None of the above Drug Transporter Examples There are hundreds of transporters in humans but only a few have well characterized effects on drug pharmacokinetics and/or drug-drug interactions P-glycoprotein OATP1B1 PEPT1 Giacomini et al. Nature Reviews: Drug Discovery. 2010. PEPT1 Peptidase transporter 1 Primarily responsible for absorption of peptides from intestine (influx) Also enables intestinal uptake of peptide-like drugs TRANSPORTER SUBSTRATES INHIBITORS LOCATION Cephalexin, valacyclovir, Intestinal PEPT1 enalapril, captopril, Glycyl-proline enterocytes, kidney peptides proximal tubules PEPT1 Plasma concentrations of acyclovir following valacyclovir PO administration are highly dependent on the presence of PEPT1 Valacyclovir is converted to acyclovir in vivo Yang et al. Drug Metab Dispos. 2013. PEPT1 Cephalexin PO Cephalexin PO + Glycyl-Proline Hironaka et al. Pharmaceutical Research. 2009.  Bacterial Drug Transporters Transporter channels permit passage of certain antibiotics across the bacterial cell wall and also cause antibiotic resistance Porin channels: allow entry of antibiotics into bacteria that are not Porin Efflux Pump capable of passive diffusion through membrane = increased intracellular antibiotic concentration Efflux pumps: remove antibiotics from cell membrane = decreased intracellular antibiotic concentration  Bacterial Drug Transporters Porin channel genes can acquire mutations thus preventing uptake of their substrates = antibiotic resistance Mutations = Loss of Function Example Porin Channels Example Substrates Porin OmpK35 Cephalosporins, cephamycins OmpK36 Cephalosporins, carbapenems, fluoroquinolones  Bacterial Drug Transporters Efflux pumps remove antibiotics and other Mutations = Loss of Function waste materials from bacterial cells Mutations or loss of function = increased antibiotic susceptibility Example Efflux Pump Example Substrates AcrB All antibiotics except aminoglycosides MexAB-OprM Most β-lactams Practice Question 3) Which one of the following transporters is responsible for aiding oral absorption of valacyclovir? A. P-gp B. OATP1B1 C. PepT1 D. OCT1 Practice Question 4) Which one of the following transporters is responsible for hepatic uptake of statins? A. P-gp B. OATP1B1 C. PepT1 D. OCT1 Practice Question 5) Which of the following are associated with bacterial resistance to an antibiotic? Select all that apply. A. Functional OmpK35 porin channel B. Nonfunctional OmpK35 porin channel C. Functional AcrB efflux pump D. Nonfunctional AcrB efflux pump E. None of the above