Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016
- 42 Downloads
Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved).
Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance.
The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends.
Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively.
The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.
The authors thank Mr. Timothy Lee, PharmD student for assistance in retrieving information for this study. The authors thank the University of Washington Drug Interaction Database, specifically Dr. Isabelle Ragueneau-Majlessi for providing feedback of the criteria for defining metabolism pathways. The authors also sincerely thank Dr. Kristina Ward for her contribution to the data extraction from the CenterWatch database.
Compliance with Ethical Standards
Support from Grant No. R15 GM101599 from the National Institutes of Health is gratefully acknowledged.
Conflict of interest
Anitha Saravanakumar, Armin Sadighi, Rachel Ryu, and Fatemeh Akhlaghi have no conflicts of interest that are directly relevant to the content of this article.
- 1.Oda S, Fukami T, Yokoi T, Nakajima M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet. 2015;30(1):30–51.Google Scholar
- 2.Iyanagi T. Molecular mechanism of phase I and phase II drug-metabolizing enzymes: implications for detoxification. Int Rev Cytol. 2007;260:35–112.Google Scholar
- 3.Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201–8.Google Scholar
- 4.Nelson DR, Zeldin DC, Hoffman SM, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. 2004;14(1):1–18.Google Scholar
- 5.Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360(9340):1155–62.Google Scholar
- 6.Sim SC, Ingelman-Sundberg M. Update on allele nomenclature for human cytochromes P450 and the human cytochrome P450 allele (CYP-allele) nomenclature database. Methods Mol Biol. 2013;987:251–9.Google Scholar
- 7.Walsky RL, Obach RS. Validated assays for human cytochrome P450 activities. Drug Metab Dispos. 2004;32(6):647–60.Google Scholar
- 8.Wienkers LC, Heath TG. Predicting in vivo drug interactions from in vitro drug discovery data. Nat Rev Drug Discov. 2005;4(10):825–33.Google Scholar
- 9.Guengerich FP, Cheng Q. Orphans in the human cytochrome P450 superfamily: approaches to discovering functions and relevance in pharmacology. Pharmacol Rev. 2011;63(3):684–99.Google Scholar
- 10.Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–5.Google Scholar
- 12.Gan J, Ma S, Zhang D. Non-cytochrome P450-mediated bioactivation and its toxicological relevance. Drug Metab Rev. 2016;48(4):473–501.Google Scholar
- 13.Foti RS, Dalvie DK. Cytochrome P450 and non-cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety and efficacy of xenobiotics. Drug Metab Dispos. 2016;44(8):1229–45.Google Scholar
- 14.Cerny MA. Prevalence of non-cytochrome P450-mediated metabolism in food and drug administration-approved oral and intravenous drugs: 2006–2015. Drug Metab Dispos. 2016;44(8):1246–52.Google Scholar
- 15.Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem. 2010;53(24):8441–60.Google Scholar
- 16.Leeson PD. Molecular inflation, attrition and the rule of five. Adv Drug Deliv Rev. 2016;101:22–33.Google Scholar
- 17.DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2012;52:249–73.Google Scholar
- 18.International Transporter Consortium, Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.Google Scholar
- 19.Kusuhara H, Sugiyama Y. In vitro-in vivo extrapolation of transporter-mediated clearance in the liver and kidney. Drug Metab Pharmacokinet. 2009;24(1):37–52.Google Scholar
- 20.Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci. 2006;27(5):425–46.Google Scholar
- 21.Symphony Health Solutions. 2015. http://symphonyhealth.com/wp-content/uploads/2015/05/Top-200-Drugs-of-2014.pdf. Accessed 18 Dec 2017.
- 22.CenterWatch. 2018. Available from: http://www.centerwatch.com/drug-information/fda-approved-drugs/year. Accessed Mar 2018.
- 23.Price DA, Blagg J, Jones L, Greene N, Wager T. Physicochemical drug properties associated with in vivo toxicological outcomes: a review. Expert Opin Drug Metab Toxicol. 2009;5(8):921–31.Google Scholar
- 24.University of Washington Metabolism and Transport Drug Interaction Database. 2019. https://sop.washington.edu/department-of-pharmaceutics/research/metabolism-and-transport-drug-interaction-database. Accessed Feb 2019.
- 25.US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 2017. Draft guidance for industry. In vitro metabolism and transporter mediated drug-drug interactions. https://www.fda.gov/downloads/Drugs/Guidances/UCM581965.pdf. Accessed Feb 2019.
- 26.Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: the University of Washington Metabolism and Transport Drug Interaction Database. Hum Genomics. 2010;5(1):61–72.Google Scholar
- 27.Yu J, Ritchie TK, Mulgaonkar A, Ragueneau-Majlessi I. Drug disposition and drug-drug interaction data in 2013 FDA new drug applications: a systematic review. Drug Metab Dispos. 2014;42(12):1991–2001.Google Scholar
- 28.Yu J, Ritchie TK, Zhou Z, Ragueneau-Majlessi I. Key findings from preclinical and clinical drug interaction studies presented in new drug and biological license applications approved by the Food and Drug Administration in 2014. Drug Metab Dispos. 2016;44(1):83–101.Google Scholar
- 29.Yu J, Zhou Z, Owens KH, Ritchie TK, Ragueneau-Majlessi I. What can be learned from recent new drug applications? A systematic review of drug interaction data for drugs approved by the US FDA in 2015. Drug Metab Dispos. 2017;45(1):86–108.Google Scholar
- 30.Tseng E, Walsky RL, Luzietti RA, Harris JJ, Kosa RE, Goosen TC, et al. Relative contributions of cytochrome CYP3A4 versus CYP3A5 for CYP3A-cleared drugs assessed in vitro using a CYP3A4-selective inactivator (CYP3cide). Drug Metab Dispos. 2014;42(7):1163–73.Google Scholar
- 31.Chen SY, Li JL, Meng FH, Wang XD, Liu T, Li J, et al. Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism: a prospective, randomized, controlled study. Clin Transplant. 2013;27(3):E272–81.Google Scholar
- 32.Thervet E, Anglicheau D, King B, Schlageter MH, Cassinat B, Beaune P, et al. Impact of cytochrome P450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation. 2003;76(8):1233–5.Google Scholar
- 33.McEuen K, Borlak J, Tong W, Chen M. Associations of drug lipophilicity and extent of metabolism with drug-induced liver injury. Int J Mol Sci. 2017;18(7):1335.Google Scholar
- 34.Leeson PD, Davis AM. Time-related differences in the physical property profiles of oral drugs. J Med Chem. 2004;47(25):6338–48.Google Scholar
- 35.Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.Google Scholar
- 36.Reichert JM. Trends in development and approval times for new therapeutics in the United States. Nat Rev Drug Discov. 2003;2(9):695–702.Google Scholar
- 37.Yang X, Gandhi YA, Duignan DB, Morris ME. Prediction of biliary excretion in rats and humans using molecular weight and quantitative structure-pharmacokinetic relationships. AAPS J. 2009;11(3):511–25.Google Scholar
- 38.Hosey CM, Broccatelli F, Benet LZ. Predicting when biliary excretion of parent drug is a major route of elimination in humans. AAPS J. 2014;16(5):1085–96.Google Scholar
- 39.Rendic S, Guengerich FP. Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem Res Toxicol. 2015;28(1):38–42.Google Scholar
- 40.Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012;165(5):1260–87.Google Scholar
- 41.Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693–705.Google Scholar
- 42.Romaine S, Bailey K, Hall A, Balmforth A. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J. 2010;10(1):1–11.Google Scholar
- 43.Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013;19(7):27–34.Google Scholar
- 44.König J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomics of human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(6):432–43.Google Scholar
- 45.Lin JH, Yamazaki M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet. 2003;42(1):59–98.Google Scholar
- 46.Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82.Google Scholar
- 47.Drugs.com. 2015. Available from: https://www.drugs.com. Accessed 18 Dec 2017.
- 48.Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem substance and compound databases. Nucleic Acids Res. 2016;44(D1):D1202–13.Google Scholar