Calcium effects and systemic exposure of vitamin D₃ analogues after topical treatment of active vitamin D₃-containing ointments in rats

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• 作者：Atsushi Hosomi^a ; ^{atsushi.hosomi@kyowa-kirin.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Maho Hirabe^a ; Takuya Tokuda^a ; Hiroaki Nakamura^a ; Toru Amano^a ; Tadao Okamoto^b
• 关键词：Vitamin D3-containing ointment ; Systemic exposure ; Skin permeation ; Hepatic metabolism ; Calcemic effect
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 October 2016
• 年：2016
• 卷：788
• 期：Complete
• 页码：98-103
• 全文大小：602 K

文摘

Topical agents containing vitamin D₃ (VD₃) analogues such as calcipotriol, maxacalcitol and tacalcitol and the combination of calcipotriol/betamethasone dipropionate (betamethasone) are prescribed for patients with psoriasis. However, they are known to occasionally cause hypercalcemia, and the frequency of hypercalcemia is suggested to vary according to the VD₃ analogue used. In this study, to address the reason for these differences, the calcemic effects of maxacalcitol-, calcipotriol- and calcipotriol/betamethasone-containing ointments in rats were evaluated. The serum calcium levels in rats treated with ointments containing maxacalcitol, but not calcipotriol or calcipotriol/betamethasone, were significantly elevated, which is consistent with clinical observations. The serum concentration of VD₃ analogue in rats treated with ointments containing calcipotriol and calcipotriol/betamethasone was lower than that in rats treated with maxacalcitol-containing ointment. Thus, the calcemic effects appear to be associated with the systemic exposure of VD₃ analogues in rats. To understand the mechanism underlying the different systemic exposures of VD₃ analogues, skin permeation and metabolic stability of VD₃ analogues were evaluated. The cumulative amount of calcipotriol permeated through rat skin was significantly lower than that of maxacalcitol. On the other hand, the metabolic clearance of calcipotriol in rat hepatocytes was higher than that of maxacalcitol. Similar results were obtained using human skin and human hepatocytes. The current study demonstrates that the lower calcemic effects of calcipotriol- and calcipotriol/betamethasone-containing ointments are caused by the low systemic exposure of calcipotriol according to low skin permeability and rapid hepatic elimination after topical application.