title: Synthesis, transport and mechanism of a type I prodrug: L-carnitine ester of prednisolone.
abstract: Aerosol glucocorticoid medications have become more and more important in treating BA (bronchial asthma). Although these agents are dosed to directly target airway inflammation, adrenocortical suppression and other systematic effects are still seen. To tackle this problem in a novel way, two L-carnitine ester derivatives of prednisolone (as the model drug), namely, PDC and PDSC, were synthesized to increase the absorption of prednisolone across the human bronchial epithelial BEAS-2B cells by the organic cation/carnitine transporter OCTN2 (SLC22A5) and then to slowly and intracellularly release prednisolone. The transport of prednisolone, PDC and PDSC into the human bronchial epithelial BEAS-2B cells was in the order PDSC > prednisolone > PDC at 37 °C. It was found that PDSC displayed 1.79-fold increase of uptake compared to prednisolone. Transport of PDSC by BEAS-2B was temperature-, time-, and Na(+)-dependent and saturable, with an apparent K(m) value of 329.74 μM, suggesting the involvement of carrier-mediated uptake. An RT-PCR study showed that organic cation/carnitine transporters OCTN1 and OCTN2 are expressed in BEAS-2B cells, but little in HEK293T cells. The order of uptake by HEK293T was prednisolone > PDC > PDSC. In addition, the inhibitory effects of organic cations such as L-carnitine, ergothioneine, TEA(+) and ipratropium on PDSC uptake in BEAS-2B cells were in the order L-carnitine > ipratropium > TEA(+) > ergothioneine, whereas their inhibitory effects on PDSC uptake in HEK293T cells were negligible. Finally, in vitro LPS-induced IL-6 production from BEAS-2B was more and longer suppressed by PDSC than prednisolone and PDC. All of these results suggested PDSC may be an attractive candidate for asthma treatment.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, PR China.
authors.forename: Jing-xin
authors.initials: JX
authors.lastname: Mo
authors.forename: San-jun
authors.initials: SJ
authors.lastname: Shi
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Zhi-rong
authors.initials: ZR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D001711:Biotransformation; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002331:Carnitine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004355:Drug Stability; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000032:analysis / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000074058:Solute Carrier Family 22 Member 5; D013379:Substrate Specificity; D013386:Succinates / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D027981:Symporters
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; C508600:IL6 protein, human; D015850:Interleukin-6; D027701:Organic Cation Transport Proteins; D011355:Prodrugs; D012333:RNA, Messenger; C109807:SLC22A4 protein, human; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D013386:Succinates; D027981:Symporters; C000599888:prednisolone succinate-carnitine; D011239:Prednisolone; D002331:Carnitine