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Biopharmaceutics and Pharmacokinetics of Timosaponin A-III by a Sensitive HPLC-MS/MS Method: Low Bioavailability Resulting from Poor Permeability and Solubility.
Wang, Hai-Qiao; Gong, Xiao-Mei; Lan, Fen; Zhang, Yi-Han; Xia, Jin-Er; Zhang, Hai; Guo, Jia-Lin; Liu, Min.
Afiliação
  • Wang HQ; Department of Traditional Chinese Medicine, South Campus, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201112, China.
  • Gong XM; Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • Lan F; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Zhang YH; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Xia JE; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
  • Zhang H; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
  • Guo JL; Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
  • Liu M; Department of Pharmacy, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Curr Pharm Biotechnol ; 22(5): 672-681, 2021.
Article em En | MEDLINE | ID: mdl-32634081
ABSTRACT

BACKGROUND:

Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential.

OBJECTIVE:

This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method.

METHODS:

Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague- Dawley rats by oral (20 mg/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system.

RESULTS:

After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III was 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 × 10-7 cm/s, indicating a difficult absorption. A strikingly high efflux transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10-6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, i.e. 30.58 µg/mL.

CONCLUSION:

Timosaponin A-III exhibited low oral bioavailability by oral and intravenous administration, which was probably caused by its low permeability and solubility. This study may provide a reference for its rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Saponinas / Esteroides / Antineoplásicos Fitogênicos Tipo de estudo: Diagnostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Curr Pharm Biotechnol Assunto da revista: BIOTECNOLOGIA / FARMACOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Saponinas / Esteroides / Antineoplásicos Fitogênicos Tipo de estudo: Diagnostic_studies Limite: Animals / Humans / Male Idioma: En Revista: Curr Pharm Biotechnol Assunto da revista: BIOTECNOLOGIA / FARMACOLOGIA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: China