Mdr1a plays a crucial role in regulating the analgesic effect and toxicity of aconitine by altering its pharmacokinetic characteristics.
Toxicol Appl Pharmacol
; 320: 32-39, 2017 04 01.
Article
em En
| MEDLINE
| ID: mdl-28193520
ABSTRACT
Aconitine (AC) is the primary bioactive/toxic alkaloid in plants of the Aconitum species. Our previous study demonstrated that Mdr1 was involved in efflux of AC. However, the mechanism by which Mdr1 regulates the efficacy/toxicity of AC in vivo remains unclear. The present study aimed to determine the effects of Mdr1a on the efficacy/toxicity and pharmacokinetics of AC in wild-type and Mdr1a-/- FVB mice. After oral administration of AC, significantly higher analgesic effect was observed in Mdr1a-/- mice (49% to 105%) compared to wild-type mice (P<0.05). The levels of s100-ß protein and creatine kinase, which indicate cerebral and myocardial damage, respectively, were also significantly increased (P<0.05) in Mdr1a-/- mice. Histopathological examination revealed that the Mdr1a-/- mice suffered from evident cerebral and myocardial damages, but the wild-type mice did not. These findings suggested that Mdr1a deficiency significantly promoted the analgesic effect of AC and exacerbated its toxicity. Pharmacokinetic experiments showed that T1/2 of AC in the Mdr1a-/- mice was significantly higher (from 87% to 300%) than that in wild-type mice (P<0.05). The distribution of AC in the brain of Mdr1a-/- mice was 2- to 32-fold higher than that in the brains of wild-type mice (P<0.05). Toxic reactions were more severe in Mdr1a-/- mice compared to wild-type mice. In conclusion, Mdr1a deficiency significantly enhanced the analgesic effect of AC and exacerbated its toxicity by upregulating its distribution to the brain and decreasing its plasma elimination rate. Thus, Mdr1a dysfunction may cause severe AC poisoning.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aconitina
/
Subfamília B de Transportador de Cassetes de Ligação de ATP
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Analgésicos
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article