Paliperidone, a relatively novel atypical antipsychotic drug, is a substrate for breast cancer resistance protein

Zhou,Yangang; Li,Huande; Xu,Ping; Sun,Li; Wang,Qing; Lu,Qiong; Yuan,Haiyan; Liu,Yiping

doi:10.3892/etm.2018.6847

Paliperidone, a relatively novel atypical antipsychotic drug, is a substrate for breast cancer resistance protein

Authors:
- Yangang Zhou
- Huande Li
- Ping Xu
- Li Sun
- Qing Wang
- Qiong Lu
- Haiyan Yuan
- Yiping Liu
View Affiliations

Affiliations: Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: October 11, 2018 https://doi.org/10.3892/etm.2018.6847
Pages: 5410-5416

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Paliperidone (PAL) is a relatively novel atypical antipsychotic drug for schizophrenia that induces markedly varying responses. Breast cancer resistance protein (BCRP) is a recently discovered member of the ATP‑binding cassette superfamily that has been used to control drug absorption, distribution and elimination, and especially to impede drug entry into the brain. To the best of our knowledge, the present study is the first to investigate the possibility of using PAL as a BCRP substrate. The intracellular accumulation and bidirectional transport were investigated using transfected 293 cell/BCRP and porcine renal endothelial cell (LLC‑PK1)/BCRP cell monolayers and BCRP overexpression was confirmed by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The in vitro affinity to BCRP was assessed in human BCRP (Arg482) membranes. The intracellular accumulation and bidirectional transport investigations demonstrated that BCRP can efflux PAL from cells and significantly decrease its cellular concentration over a concentration range of 0.1‑50 µM. The in vitro affinity experiments indicated that PAL has a moderate affinity to BCRP at 0.1‑100 µM. These results together suggest that PAL is a substrate for BCRP and that it can affect the blood‑brain barrier penetration of PAL at therapeutic dosages.

View Figures

View References

1	Tandon R, Belmaker RH, Gattaz WF, Lopez-Ibor JJ Jr, Okasha A, Singh B, Stein DJ and Olie JP: Fleischhacker WW and Moeller HJ; Section of Pharmacopsychiatry, World Psychiatric Association: World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res. 100:20–38. 2008. View Article : Google Scholar : PubMed/NCBI
2	Chong HY, Teoh SL, Wu DB, Kotirum S, Chiou CF and Chaiyakunapruk N: Global economic burden of schizophrenia: A systematic review. Neuropsychiatr Dis Treat. 12:357–373. 2016.PubMed/NCBI
3	Samara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, Salanti G and Leucht S: Efficacy, acceptability, and tolerability of antipsychotics in treatment-resistant schizophrenia: A network meta-analysis. JAMA Psychiatry. 73:199–210. 2016. View Article : Google Scholar : PubMed/NCBI
4	Owen MJ, Sawa A and Mortensen PB: Schizophrenia. Lancet. 388:86–97. 2016. View Article : Google Scholar : PubMed/NCBI
5	Suzuki T, Remington G, Mulsant BH, Rajji TK, Uchida H, Graff-Guerrero A and Mamo DC: Treatment resistant schizophrenia and response to antipsychotics: A review. Schizophr Res. 133:54–62. 2011. View Article : Google Scholar : PubMed/NCBI
6	Chwieduk CM and Keating GM: Paliperidone extended release: A review of its use in the management of schizophrenia. Drugs. 70:1295–1317. 2010. View Article : Google Scholar : PubMed/NCBI
7	Wang SM, Han C, Lee SJ, Patkar AA, Pae CU and Fleischhacker WW: Paliperidone: A review of clinical trial data and clinical implications. Clin Drug Investig. 32:497–512. 2012. View Article : Google Scholar : PubMed/NCBI
8	Nussbaum AM and Stroup TS: Paliperidone for treatment of schizophrenia. Schizophr Bull. 34:419–422. 2008. View Article : Google Scholar : PubMed/NCBI
9	Spina E and Cavallaro R: The pharmacology and safety of paliperidone extended-release in the treatment of schizophrenia. Expert Opin Drug Saf. 6:651–662. 2007. View Article : Google Scholar : PubMed/NCBI
10	Breedvel P, Benjnen JH and Schellens JH: Use of P-glycoprotein and BCRP inhibitors to improve oral bioavailability and CNS penetration of anticancer drugs. Trends Pharmacol Sci. 27:17–24. 2006. View Article : Google Scholar : PubMed/NCBI
11	Ueno M, Nakagawa T, Wu B, Onodera M, Huang CL, Kusaka T, Araki N and Sakamoto H: Transporters in the brain endothelial barrier. Curr Med Chem. 17:1125–1138. 2010. View Article : Google Scholar : PubMed/NCBI
12	Begley DJ: ABC transporters and the blood-brain barrier. Curr Pharm Des. 10:1295–1312. 2004. View Article : Google Scholar : PubMed/NCBI
13	Vermeir M, Naessens I, Remmerie B, Mannens G, Hendrickx J, Sterkens P, Talluri K, Boom S, Eerdekens M, van Osselaer N and Cleton A: Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans. Drug Metab Dispos. 36:769–779. 2008. View Article : Google Scholar : PubMed/NCBI
14	Suzuki Y, Tsuneyama N, Fukui N, Sugai T, Watanabe J, Ono S, Saito M and Someya T: Impact of the ABCB1 gene polymorphism on plasma 9-hydroxyrisperidone and active moiety levels in Japanese patients with schizophrenia. J Clin Psychopharmacol. 33:411–414. 2013. View Article : Google Scholar : PubMed/NCBI
15	Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS and DeVane CL: The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein. Int J Neuropsychopharmacol. 7:415–419. 2004. View Article : Google Scholar : PubMed/NCBI
16	Jani M, Ambrus C, Magnan R, Jakab KT, Beéry E, Zolnerciks JK and Krajcsi P: Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. Arch Toxicol. 88:1205–1248. 2014. View Article : Google Scholar : PubMed/NCBI
17	Wang JS, Zhu HJ, Markowitz JS, Donovan JL, Yuan HJ and Devane CL: Antipsychotic drugs inhibit the function of breast cancer resistance protein. Basic Clin Pharmacol Toxicol. 103:336–341. 2008. View Article : Google Scholar : PubMed/NCBI
18	Tian Y, Qu BX, Yao Y and Zeng S: Establishment of BCRP expressed pig kidney cell line LLC-PK1/BCRP and its biological profile. Yao Xue Xue Bao. 47:1599–1604. 2012.(In Chinese). PubMed/NCBI
19	Yan H, Zhang DY, Li X, Yuan XQ, Yang YL, Zhu KW, Zeng H, Li XL, Cao S, Zhou HH, et al: Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution. Leuk Lymphoma. 58:1948–1957. 2017. View Article : Google Scholar : PubMed/NCBI
20	Feng B, Mills JB, Davidson RE, Mireles RJ, Janiszewski JS, Troutman MD and de Morais SM: In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system. Drug Metab Dispos. 36:268–275. 2008. View Article : Google Scholar : PubMed/NCBI
21	Boulton DW, DeVane CL, Liston HL and Markowitz JS: In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 71:163–169. 2002. View Article : Google Scholar : PubMed/NCBI
22	Kim KA, Joo HJ, Lee HM and Park JY: Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers. Pharmacogenet Genomics. 24:35–42. 2014. View Article : Google Scholar : PubMed/NCBI
23	Hoosain FG, Choonara YE, Tomar LK, Kumar P, Tyagi C, du Toit LC and Pillay V: Bypassing P-glycoprotein drug efflux mechanisms: Possible applications in pharmacoresistant schizophrenia therapy. Biomed Res Int. 2015:4849632015. View Article : Google Scholar : PubMed/NCBI
24	Tian Y, Qian S, Jiang Y, Shen Q, Zheng J, Zhou H and Zeng S: The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids. Int J Pharm. 453:371–379. 2013. View Article : Google Scholar : PubMed/NCBI
25	Takada T, Suzuki H and Sugiyama Y: Characterization of polarized expression of point- or deletion-mutated human BCRP/ABCG2 in LLC-PK1 cells. Pharm Res. 22:458–464. 2005.Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 39:361–398, 1999. View Article : Google Scholar : PubMed/NCBI
26	Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 39:361–98. 1999. View Article : Google Scholar : PubMed/NCBI
27	Hrycyna CA, Ramachandra M, Ambudkar SV, Ko YH, Pedersen PL, Pastan I and Gottesman MM: Mechanism of action of human P-glycoprotein ATPase activity. Photochemical cleavage during a catalytic transition state using orthovanadate reveals cross-talk between the two ATP sites. J Biol Chem. 273:16631–16634. 1998.
28	Ozvegy-Laczka C, Köblös G, Sarkadi B and Váradi A: Single amino acid (482) variants of the ABCG2 multidrug transporter: Major differences in transport capacity and substrate recognition. Biochim Biophys Acta. 1668:53–63. 2005. View Article : Google Scholar : PubMed/NCBI
29	Shukla S, Robey RW, Bates SE and Ambudkar SV: The calcium channel blockers, 1,4-dihydropyridines, are substrates of the multidrug resistance-linked ABC drug transporter, ABCG2. Biochemistry. 45:8940–8951. 2006. View Article : Google Scholar : PubMed/NCBI
30	Eddabra L, Wenner T, El Btaouri H, Baranek T, Madoulet C, Cornillet-Lefebvre P and Morjani H: Arginine 482 to glycine mutation in ABCG2/BCRP increases etoposide transport and resistance to the drug in HEK-293 cells. Oncol Rep. 27:232–237. 2012.PubMed/NCBI
31	de Leon J, Wynn G and Sandson NB: The pharmacokinetics of paliperidone versus risperidone. Psychosomatics. 51:80–88. 2010. View Article : Google Scholar : PubMed/NCBI
32	Lindenmayer JP and Kaur A: Antipsychotic management of schizoaffective disorder: A review. Drugs. 76:589–604. 2016. View Article : Google Scholar : PubMed/NCBI