Journal name: Clinical Pharmacology: Advances and Applications Article Designation: Review Year: 2018 Volume: 10 Clinical Pharmacology: Advances and Applications Dovepress Running head verso: Roberts and Gibbs Running head recto: Complex drug–drug interactions open access to scientific and medical research DOI: http://dx.doi.org/10.2147/CPAA.S146115 Open Access Full Text Article REVIEW Mechanisms and the clinical relevance of complex drug–drug interactions Arthur G Roberts Abstract: As a result of an increasing aging population, the number of individuals taking mul- Morgan E Gibbs tiple medications simultaneously has grown considerably. For these individuals, taking multiple medications has increased the risk of undesirable drug–drug interactions (DDIs), which can Pharmaceutical and Biomedical Sciences, University of Georgia, cause serious and debilitating adverse drug reactions (ADRs). A comprehensive understanding Athens, GA, USA of DDIs is needed to combat these deleterious outcomes. This review provides a synopsis of the pharmacokinetic (PK) and pharmacodynamic (PD) mechanisms that underlie DDIs. PK-mediated DDIs affect all aspects of drug disposition: absorption, distribution, metabolism and excretion (ADME). In this review, the cells that play a major role in ADME and have been investigated for DDIs are discussed. Key examples of drug metabolizing enzymes and drug transporters that For personal use only. are involved in DDIs and found in these cells are described. The effect of inhibiting or inducing these proteins through DDIs on the PK parameters is also reviewed. Despite most DDI studies being focused on the PK effects, DDIs through PD can also lead to significant and harmful effects. Therefore, this review outlines specific examples and describes the additive, synergistic and antagonistic mechanisms of PD-mediated DDIs. The effects DDIs on the maximum PD response (Emax) and the drug dose or concentration (EDEC50) that lead to 50% of Emax are also examined. Significant gaps in our understanding of DDIs remain, so innovative and emerging approaches are critical for overcoming them. Keywords: inhibition, induction, synergism, additive, antagonism, adverse drug reactions, ADRs Introduction The aging population in the USA is expected to rise in the foreseeable future and this group often deals with multiple health conditions.1,2 To treat these multiple health Clinical Pharmacology: Advances and Applications downloaded from https://www.dovepress.com/ by 54.70.40.11 on 19-Dec-2018 conditions, individuals within this group have been required to take two or more pre- scription drugs simultaneously. This has led to a significant increase in the number of Americans that need to take multiple medications.3 For those over 65 years old, nearly half take more than five drugs simultaneously.4 In many cases, these individuals take drugs that they do not need.4 Ultimately, taking multiple medications simultaneously increases an individual’s risk for undesirable drug–drug interactions (DDIs) that lead to serious and debilitating adverse drug reactions (ADRs).5–7 Correspondence: Arthur G Roberts A comprehensive understanding of DDIs is critical for safer coadministration of Pharmaceutical and Biomedical Sciences, drugs and reduced risk of ADRs. In this review, a synopsis of the pharmacokinetic University of Georgia, 240 W. Green Street, Athens, GA 30602, USA (PK) and pharmacodynamic (PD) mechanisms that underlie DDIs is provided. In this Tel +1 706 542 7787 work, the drug that causes the DDI will be called the “perpetrator” drug, while the Fax +1 706 542 5358 Email [email protected] drug of interest will be called the “victim” drug.8–10 In PK, DDIs touch all aspects of submit your manuscript | www.dovepress.com Clinical Pharmacology: Advances and Applications 2018:10 123–134 123 Dovepress © 2018 Roberts and Gibbs. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/CPAA.S146115 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Roberts and Gibbs Dovepress drug disposition: absorption, distribution, metabolism and A Enterocyte excretion (ADME). This review will discuss the cells that play a role in each aspect of ADME and have been the focus Pgp of DDI investigations. DDIs through PK occur through drug BCRP CYP3A4 metabolizing enzymes and drug transporters that are found Lumen Portal vein within these cells. This work provides representative DDI OATP1A2 examples with a few key proteins and examines their effect on PK parameters. Although most current investigations have focused on how PK is affected by DDIs, significant DDIs have B Brain endothelial cell also been noted with PD. DDIs through PD can occur through Pgp additive, synergistic and antagonistic mechanisms. Several BCRP illustrative examples of DDIs from each of these mechanisms e is provided in this work. Their effect on the maximum PD MRP4 OAT3 spac response (E ) and the drug dose or concentration at 50% OAT3 max Blood stream MCT1 Brain interstitial of Emax (EDEC50) is discussed. OATP1A2 Pharmacokinetics (PK) PK is what the body does to a drug and it includes ADME.11 C Placental trophoblast Depending on the process of ADME that is affected, PK- mediated DDIs can lead to elevated free plasma concentra- Pgp tions of the “victim” drug that can cause undesirable ADRs blood and toxicity. They can also lead to depressed free plasma Maternal concentrations of the “victim” drug and reduced therapeutic CYP19 Fetal blood For personal use only. efficacy. The major cells, drug-metabolizing enzymes and D drug transporters that have been implicated in DDIs and are discussed in this work are shown in Figure 1. The effect of Hepatocyte Hepatocyte DDIs on the PK is described below and summarized with additional detail in Table 1. Pgp CYP3A4 Bile Absorption Blood CYP1A2 Blood Drug absorption can occur through both oral and extraoral Pgp Pgp UGT2B7 11 routes such as through the skin. Because oral drug adminis- Biliary Pgp Biliary tration is the preferred route for administration,11 this review endothelial endothelial Pgp cell is focused on drug absorption through the gastrointestinal cell (GI) tract. The GI tract is composed of the mouth, esophagus, E Renal proximal tubule cell stomach, small intestines and the colon.11 Of these anatomical Clinical Pharmacology: Advances and Applications downloaded from https://www.dovepress.com/ by 54.70.40.11 on 19-Dec-2018 structures, most of the drug absorption occurs in the small Pgp OAT1 intestines as a result of its relatively large surface area.11,12 d e OAT3 The large surface area is due in large part to cells that contain Urin Bloo microvilli called enterocytes that line the small intestine.11,12 OCTs Drug absorption in these cells is controlled by passive diffu- sion across the plasma membrane and the presence of drug Figure 1 Drug-metabolizing enzymes and drug transporters in (A) an enterocyte, metabolizing enzymes and drug transporters (Figure 1).11 (B) a brain endothelial cell, (C) a placental trophoblast, (D) hepatocyte and biliary endothelial cells, and (E) a renal proximal tubule cell. Notes: The drug metabolizing enzymes are shown as blue circles and the Drug transporters transporters are shown as arrows. The direction of the arrow reflects the direction There are many drug transporters on the apical (lumen-side) of transport. Abbreviations: BCRP, breast cancer resistance protein; CYP1A2, CYP/CYP450 and basal (blood-side) membrane surfaces of the enterocytes 1A2; CYP3A4, CYP/CYP450 3A4; MCT1, monocarboxylate transporter 1; OAT1, (Figure 1).13 Two highly expressed drug efflux transporters organic anionic transporter 1; OAT3, organic anionic transporter 3; OATP1A2, organic anionic transporting polypeptide 1A2; OCTs, organic cationic transporters; on the apical side of the enterocytes are Pgp and the BCRP.14 MRP4, multidrug resistance protein 4; Pgp, P-glycoprotein. 124 submit your manuscript | www.dovepress.com Clinical Pharmacology: Advances and Applications 2018:10 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Complex drug–drug interactions Table 1 Pharmacokinetically mediated DDIs ADME Protein “Victim” drug “Perpetrator” drug DDI PK effect Ref Intestinal absorption Pgp Talinolol Erythromycin Inhibition AUC: increased 20 Cmax: increased F: increased Intestinal absorption Pgp Talinolol Rifampicin Induction AUC: decreased 35% 21 Cmax: decreased 38% F: decreased 35% Intestinal absorption BCRP Rosuvastatin Fostamatinib Inhibition AUC: increased 196% 22,23 Cmax: increased 188% F: increased Intestinal absorption OATP1A2 Fexofenadine Naringin Inhibition AUC: decreased 22% 24 Cmax: decreased 18% F: decreased Intestinal absorption CYP3A4 Midazolam Itraconazole Inhibition AUC: increased 33 Fg: increased Intestinal absorption CYP3A4 Alfentanil Troleandomycin Inhibition AUC: increased 34 Cmax: increased Fg: increased Intestinal absorption CYP3A4 Alfentanil Rifampicin Induction AUC: decreased 34 Cmax: decreased Fg: decreased BBB distribution Pgp Verapamil Tariquidar