In vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D₂: Is this a new immediate-release therapeutic option for niacin?

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• 作者：Mark T. Ledwidge^a ; ^b ; ¹ ; Fiona Ryan^b ; David M. Kerins^c ; ^d ; Damian O&rsquo ; Connell^d ; Gene Cefali^b ; Shona Harmon^e ; Michael Jones^e ; John F. Gilmer^b ; ^e ; ¹ ; ^{gilmerjf@tcd.ie}
• 关键词：ApoB ; apolipoprotein B ; AUC ; area under the curve ; BuChE ; butyrylcholinesterase ; COX ; cyclooxygenase ; SR ; sustained release ; ER ; extended release ; GPCR ; G-protein coupled receptor ; HDL-C ; high density lipoprotein cholesterol ; IR ; immediate-release ; LDL-C
• 刊名：Atherosclerosis
• 出版年：2012
• 期刊代码：28_00219150
• 类别：med
• 出版时间：April, 2012
• 卷：221
• 期：2
• 页码：478-483
• 文件大小：464 K

摘要

lass="h4">Objectives

To evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs).

lass="h4">Methods

We compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D₂, ex vivo thromboxane B₂ (TXB₂) levels and plasma pharmacokinetics.

lass="h4">Results

ST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T_max values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38%and 40%reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32%and 25%for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB₂ generation was suppressed at 15 min and complete suppression of TXB₂ was sustained at 24 h (p < 0.01 vs niacin). ST0702 suppressed PGD₂ exposure eightfold (p = 0.012) compared to niacin over the first 24 h.

lass="h4">Conclusions

This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB₂ and PGD₂ increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin.