Do P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier impact morphine brain distribution?

Kotlinska-Lemieszek A, Klepstad P, Faksvåg Haugen D (2015) Clinically significant drug-drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review. Drug Des Devel Ther 5255. https://doi.org/10.2147/DDDT.S86983

Taskar KS, Yang X, Neuhoff S, Patel M, Yoshida K, Paine MF, Brouwer KLR, Chu X, Sugiyama Y, Cook J, Polli JW, Hanna I, Lai Y, Zamek-Gliszczynski M (2022) Clinical relevance of hepatic and renal P-gp/BCRP inhibition of drugs: an International Transporter Consortium Perspective. Clin Pharmacol Ther 112:573–592. https://doi.org/10.1002/cpt.2670

Article  CAS  PubMed  Google Scholar 

Food and Drug Administration (2017) In vitro metabolism- and transporter-mediated drug-drug Interaction studies Guidance for Industry. FDA Guidel 47

ICH (2022) ICH Harmonised Guideline – Drug Interaction studies (M12). Int Counc Harmon Tech Requir Pharm Hum Use 31:1–69

Google Scholar 

Gerber W, Steyn JD, Kotzé AF, Hamman JH (2018) Beneficial pharmacokinetic drug interactions: a tool to improve the bioavailability of poorly permeable drugs. Pharmaceutics 10:1–15. https://doi.org/10.3390/pharmaceutics10030106

Article  CAS  Google Scholar 

Kalvass JC, Polli JW, Bourdet DL, Feng B, Huang SM, Liu X, Smith QR, Zhang LK, Zamek-Gliszczynski MJ (2013) Why clinical modulation of efflux transport at the human blood-brain barrier is unlikely: the ITC evidence-based position. Clin Pharmacol Ther 94:80–94. https://doi.org/10.1038/clpt.2013.34

Article  CAS  PubMed  Google Scholar 

Sanchez-Covarrubias L, Slosky L, Thompson B, Davis T, Ronaldson P (2014) Transporters at CNS barrier sites: Obstacles or opportunities for Drug Delivery? Curr Pharm Des 20:1422–1449. https://doi.org/10.2174/13816128113199990463

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wagner CC, Bauer M, Karch R, Feurstein T, Kopp S, Chiba P, Kletter K, Löscher W, Müller M, Zeitlinger M, Langer O (2009) A pilot study to assess the efficacy of tariquidar to inhibit P-glycoprotein at the human blood-brain barrier with (R)-11 C- verapamil and PET. J Nucl Med 50:1954–1961. https://doi.org/10.2967/jnumed.109.063289

Article  PubMed  Google Scholar 

Sasongko L, Link JM, Muzi M, Mankoff DA, Yang X, Collier AC, Shoner SC, Unadkat JD (2005) Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther 77:503–514. https://doi.org/10.1016/j.clpt.2005.01.022

Article  CAS  PubMed  Google Scholar 

Xie R, Hammarlund-Udenaes M, De Boer AG, De Lange ECM (1999) The role of P-glycoprotein in blood-brain barrier transport of morphine: Transcortical microdialysis studies in mdr1a (-/-)and mdr1a (+/+) mice. Br J Pharmacol 128:563–568. https://doi.org/10.1038/sj.bjp.0702804

Article  CAS  PubMed  PubMed Central  Google Scholar 

Groenendaal D, Freijer J, De Mik D, Bouw MR, Danhof M, De Lange ECM (2007) Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux. Br J Pharmacol 151:701–712. https://doi.org/10.1038/sj.bjp.0707257

Article  CAS  PubMed  PubMed Central  Google Scholar 

Letrent SP, Pollack GM, Brouwer KR, Brouwer KLR (1999) Effects of a potent and specific P-glycoprotein inhibitor on the blood- brain barrier distribution and antinoclceptive effect of morphine in the rat. Drug Metab Dispos 27:827–834

Article  CAS  PubMed  Google Scholar 

Chaves C, Remiao F, Cisternino S, Decleves X (2017) Opioids and the blood-brain barrier: a dynamic Interaction with consequences on Drug Disposition in Brain. Curr Neuropharmacol 15:1156–1173. https://doi.org/10.2174/1570159x15666170504095823

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tunblad K, Hammarlund-Udenaes M, Jonsson EN (2005) Influence of probenecid on the delivery of morphine-6-glucuronide to the brain. Eur J Pharm Sci 24:49–57. https://doi.org/10.1016/j.ejps.2004.09.009

Article  CAS  PubMed  Google Scholar 

Löscher W, Potschka H (2005) Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2:86–98. https://doi.org/10.1602/neurorx.2.1.86

Article  PubMed  PubMed Central  Google Scholar 

Letrent SP, Polli JW, Humphreys JE, Pollack GM, Brouwer KR, Brouwer KLR (1999) P-glycoprotein-mediated transport of morphine in brain capillary endothelial cells. Biochem Pharmacol 58:951–957. https://doi.org/10.1016/S0006-2952(99)00180-X

Article  CAS  PubMed  Google Scholar 

Kervezee L, Hartman R, van den Berg DJ, Meijer JH, de Lange ECM (2017) Diurnal variation in the pharmacokinetics and brain distribution of morphine and its major metabolite. Eur J Pharm Sci 109:S132–S139. https://doi.org/10.1016/j.ejps.2017.05.048

Article  CAS  Google Scholar 

Gülave B, Budda D, Saleh MA, van Hasselt JC, de Lange EC (2023) Does nonlinear blood-brain barrier transport matter for (lower) morphine dosing strategies? Eur J Pharm Sci 187:106482. https://doi.org/10.1016/j.ejps.2023.106482

Article  CAS  PubMed  Google Scholar 

Saleh MAA, Loo CF, Elassaiss-Schaap J, De Lange ECM (2021) Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations. J Pharmacokinet Pharmacodyn 48:725–741. https://doi.org/10.1007/s10928-021-09768-7

Article  CAS  PubMed  PubMed Central  Google Scholar 

Oosten AW, Abrantes JA, Jönsson S, Matic M, van Schaik RHN, de Bruijn P, van der Rijt CCD, Mathijssen RHJ (2017) A prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer patients. Clin Pharmacokinet 56:733–746. https://doi.org/10.1007/s40262-016-0471-7

Article  CAS  PubMed  Google Scholar 

Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Iynkkaran NAI, Liu Y, Maciejewski A, Gale N, AlexWilson, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M (2017) DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 46:D1074–D1082. https://doi.org/10.1093/nar/gkx1037

Article  CAS  PubMed Central  Google Scholar 

Al-Majdoub ZM, Al Feteisi H, Achour B, Warwood S, Neuhoff S, Rostami-Hodjegan A, Barber J (2019) Proteomic quantification of Human Blood-Brain Barrier SLC and ABC Transporters in healthy individuals and dementia patients. Mol Pharm 16:1220–1233. https://doi.org/10.1021/acs.molpharmaceut.8b01189

Article  CAS  PubMed  Google Scholar 

Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, Terasaki T, Scherrmann JM (2011) Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels. Mol Pharm 8:1332–1341. https://doi.org/10.1021/mp200129p

Article  CAS  PubMed  Google Scholar 

Uchida Y, Ohtsuki S, Katsukura Y, Ikeda C, Suzuki T, Kamiie J, Terasaki T (2011) Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors. J Neurochem 117:333–345. https://doi.org/10.1111/j.1471-4159.2011.07208.x

Article  CAS  PubMed  Google Scholar 

Al Feteisi H, Al-Majdoub ZM, Achour B, Couto N, Rostami-Hodjegan A, Barber J (2018) Identification and quantification of blood–brain barrier transporters in isolated rat brain microvessels. J Neurochem 146:670–685. https://doi.org/10.1111/jnc.14446

Article  CAS  PubMed  Google Scholar 

Hoshi Y, Uchida Y, Tachikawa M, Inoue T, Ohtsuki S, Terasaki T (2013) Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset. J Pharm Sci 102:3343–3355. https://doi.org/10.1002/jps.23575

Article  CAS  PubMed  Google Scholar 

Mendez D, Gaulton A, Bento AP, Chambers J, De Veij M, Félix E, Magariños MP, Mosquera JF, Mutowo P, Nowotka M, Gordillo-Marañón M, Hunter F, Junco L, Mugumbate G, Rodriguez-Lopez M, Atkinson F, Bosc N, Radoux CJ, Segura-Cabrera A, Hersey A, Leach AR (2019) ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res 47:D930–D940. https://doi.org/10.1093/nar/gky1075

Article  CAS  PubMed  Google Scholar 

Rowland M, Matin SB (1973) Kinetics of drug-drug interactions. J Pharmacokinet Biopharm 1:553–567. https://doi.org/10.1007/BF01059791

Article  CAS  Google Scholar 

Peng Y, Cheng Z, Xie F (2021) Evaluation of pharmacokinetic drug-drug interactions: a review of the mechanisms, in vitro and in silico approaches. Metabolites 11:1–16. https://doi.org/10.3390/metabo11020075

Comments (0)

No login
gif