Increased Penetration of Diphenhydramine in Brain Via Proton-coupled Organic Cation Antiporter in Rats with Lipopolysaccharide-induced Inflammation

Overview

Journal Brain Behav Immun Health

Date 2021 Sep 30

PMID 34589723

Citations 5

Authors

Atsushi Kawase

Taihei Chuma

Kota Irie

Akira Kazaoka

Asuka Kakuno

Naoya Matsuda

Hiroaki Shimada

Masahiro Iwaki

Affiliations

Soon will be listed here.

Abstract

Uptake transporters in brain microvascular endothelial cells (BMECs) are involved in the penetration of basic (cationic) drugs such as diphenhydramine (DPHM) into the brain. Lipopolysaccharide (LPS)-induced inflammation alters the expression levels and activities of uptake transporters, which change the penetration of DPHM into the brain. A brain microdialysis study showed that the unbound brain-to-plasma partition coefficient ( ) for DPHM in LPS rats was approximately two times higher than that in control rats. The transcellular transport of DPHM to BMECs was increased when BMECs were cultured with serum from LPS rats. Compared with control rats or BMECs, the brain uptake of DPHM in LPS rats was increased and the intracellular accumulation of DPHM was increased under a high intracellular pH in BMECs from LPS rats, respectively. Treatment of BMECs with transporter inhibitors or inflammatory cytokines had little impact on the intracellular accumulation of DPHM in BMECs. This study suggests that LPS-induced inflammation promotes unidentified proton-coupled organic cation (H/OC) antiporters that improve the penetration of DPHM into rat brain via the blood-brain barrier.

Citing Articles

Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics.

Ballgren F, Hammarlund-Udenaes M, Loryan I Fluids Barriers CNS. 2024; 21(1):95.

PMID: 39623471 PMC: 11613587. DOI: 10.1186/s12987-024-00598-6.

Region-independent active CNS net uptake of marketed H/OC antiporter system substrates.

Ballgren F, Hu Y, Li S, van de Beek L, Hammarlund-Udenaes M, Loryan I Front Cell Neurosci. 2024; 18:1493644.

PMID: 39534684 PMC: 11554538. DOI: 10.3389/fncel.2024.1493644.

Active CNS delivery of oxycodone in healthy and endotoxemic pigs.

Ballgren F, Bergfast T, Ginosyan A, Mahajan J, Lipcsey M, Hammarlund-Udenaes M Fluids Barriers CNS. 2024; 21(1):86.

PMID: 39443944 PMC: 11515623. DOI: 10.1186/s12987-024-00583-z.

The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells.

Svane N, Pedersen A, Rodenberg A, Ozgur B, Saaby L, Bundgaard C Fluids Barriers CNS. 2024; 21(1):39.

PMID: 38711118 PMC: 11071266. DOI: 10.1186/s12987-024-00544-6.

Differences in Cerebral Distribution between Imipramine and Paroxetine via Membrane Transporters at the Rat Blood-Brain Barrier.

Akanuma S, Han M, Murayama Y, Kubo Y, Hosoya K Pharm Res. 2022; 39(2):223-237.

PMID: 35112227 DOI: 10.1007/s11095-022-03179-0.

References

Kato R, Yamashita S, Moriguchi J, Nakagawa M, Tsukura Y, Uchida K . Changes of midazolam pharmacokinetics in Wistar rats treated with lipopolysaccharide: relationship between total CYP and CYP3A2. Innate Immun. 2008; 14(5):291-7. DOI: 10.1177/1753425908095956. View

Bruss M, Bonisch H . Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 2002; 136(6):829-36. PMC: 1573414. DOI: 10.1038/sj.bjp.0704785. View

Auvity S, Chapy H, Goutal S, Caille F, Hosten B, Smirnova M . Diphenhydramine as a selective probe to study H-antiporter function at the blood-brain barrier: Application to [C]diphenhydramine positron emission tomography imaging. J Cereb Blood Flow Metab. 2016; 37(6):2185-2195. PMC: 5464711. DOI: 10.1177/0271678X16662042. View

Bolder U, Jeschke M, Landmann L, Wolf F, de Sousa C, Schlitt H . Heat stress enhances recovery of hepatocyte bile acid and organic anion transporters in endotoxemic rats by multiple mechanisms. Cell Stress Chaperones. 2006; 11(1):89-100. PMC: 1400616. DOI: 10.1379/csc-143r.1. View

Au-Yeung S, Rurak D, Gruber N, Riggs K . A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: potential involvement of a carrier-mediated mechanism. Drug Metab Dispos. 2006; 34(6):955-60. DOI: 10.1124/dmd.105.007898. View

Chapy H, Goracci L, Vayer P, Parmentier Y, Carrupt P, Decleves X . Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line. Br J Pharmacol. 2015; 172(20):4888-904. PMC: 4621989. DOI: 10.1111/bph.13258. View

Okura T, Ito R, Ishiguro N, Tamai I, Deguchi Y . Blood-brain barrier transport of pramipexole, a dopamine D2 agonist. Life Sci. 2007; 80(17):1564-71. DOI: 10.1016/j.lfs.2007.01.035. View

Spector R . Transport of amantadine and rimantadine through the blood-brain barrier. J Pharmacol Exp Ther. 1988; 244(2):516-9. View

Perry V . Innate inflammation in Parkinson's disease. Cold Spring Harb Perspect Med. 2012; 2(9):a009373. PMC: 3426823. DOI: 10.1101/cshperspect.a009373. View

10.

Kitamura A, Higuchi K, Okura T, Deguchi Y . Transport characteristics of tramadol in the blood-brain barrier. J Pharm Sci. 2014; 103(10):3335-41. DOI: 10.1002/jps.24129. View

11.

Oshima S, Nemoto E, Kuramochi M, Saitoh Y, Kobayashi D . Penetration of oseltamivir and its active metabolite into the brain after lipopolysaccharide-induced inflammation in mice. J Pharm Pharmacol. 2009; 61(10):1397-400. DOI: 10.1211/jpp/61.10.0018. View

12.

Kitamura A, Okura T, Higuchi K, Deguchi Y . Cocktail-Dosing Microdialysis Study to Simultaneously Assess Delivery of Multiple Organic-Cationic Drugs to the Brain. J Pharm Sci. 2015; 105(2):935-940. DOI: 10.1002/jps.24691. View

13.

Sadiq M, Borgs A, Okura T, Shimomura K, Kato S, Deguchi Y . Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. J Pharm Sci. 2011; 100(9):3912-23. DOI: 10.1002/jps.22567. View

14.

Wen G, Ringseis R, Eder K . Mouse OCTN2 is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha) via a PPRE located in the first intron. Biochem Pharmacol. 2009; 79(5):768-76. DOI: 10.1016/j.bcp.2009.10.002. View

15.

Gengo F, Gabos C, Miller J . The pharmacodynamics of diphenhydramine-induced drowsiness and changes in mental performance. Clin Pharmacol Ther. 1989; 45(1):15-21. DOI: 10.1038/clpt.1989.3. View

16.

Somann J, Wasilczuk K, Neihouser K, Sturgis J, Albors G, Robinson J . Characterization of plasma cytokine response to intraperitoneally administered LPS & subdiaphragmatic branch vagus nerve stimulation in rat model. PLoS One. 2019; 14(3):e0214317. PMC: 6438475. DOI: 10.1371/journal.pone.0214317. View

17.

S L, Chaudhary S, R S R . Hydroalcoholic extract of Stevia rebaudiana bert. leaves and stevioside ameliorates lipopolysaccharide induced acute liver injury in rats. Biomed Pharmacother. 2017; 95:1040-1050. DOI: 10.1016/j.biopha.2017.08.082. View

18.

Poller B, Drewe J, Krahenbuhl S, Huwyler J, Gutmann H . Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell Mol Neurobiol. 2009; 30(1):63-70. PMC: 11498628. DOI: 10.1007/s10571-009-9431-1. View

19.

Uno S, Kawase A, Tsuji A, Tanino T, Iwaki M . Decreased intestinal CYP3A and P-glycoprotein activities in rats with adjuvant arthritis. Drug Metab Pharmacokinet. 2007; 22(4):313-21. DOI: 10.2133/dmpk.22.313. View

20.

Qin L, Wu X, Block M, Liu Y, Breese G, Hong J . Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007; 55(5):453-62. PMC: 2871685. DOI: 10.1002/glia.20467. View