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Intravenous and subcutaneous toxicity and absorption kinetics in mice and dogs of the antileishmanial triterpene saponin PX-6518.

ABSTRACT: The intravenous (IV) and subcutaneous (SC) toxicity and absorption kinetics of the antileishmanial triterpene saponin PX-6518 and its active constituents maesabalide-III and -IV were studied in mice and dogs. A high-dose wash-out study of PX-6518 at 20 mg/kg SC for 5 days and a single low-dose wash-out study at 1, 2.5 or 5 mg/kg SC and IV with follow-up until day 35 after treatment were performed in mice. Beagle dogs received three escalating doses of maesabalide-III and -IV at weekly intervals (0.01, 0.1 and 0.5 mg/kg IV and maesabalide-III was also dosed SC at 0.1, 0.2 and 0.4 mg/kg). Endpoint measurements included clinical, hematological and serum biochemical parameters. Pathology and toxicokinetic studies were performed on the dogs. Whereas the neutrophils and aspartate aminotransferase and alanine aminotransferase levels were increased in the high-dose wash-out mouse study, these parameters did not change in the low-dose wash-out study. The dogs were far more susceptible than mice to liver toxicity (hepatocellular necrosis and elevated liver enzymes) and developed a painful inflammatory reaction at the SC injection site. Toxicokinetic analysis revealed a non dose-linear systemic availability with plasma concentrations above the antileishmanial IC?? after only a single dose at 0.01 mg/kg IV or 0.1 mg/kg SC. Related to the long half-life (T(1/2) 71-91 h after SC dosing), repeated dosing at weekly intervals may result in drug accumulation and enhanced toxicity. It was decided not to pursue further drug development for PX-6518 because of the hepatotoxic risk.

SUBMITTER: Maes L

PROVIDER: S-EPMC6269738 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Intravenous and subcutaneous toxicity and absorption kinetics in mice and dogs of the antileishmanial triterpene saponin PX-6518.

Maes Louis L

Molecules (Basel, Switzerland) 20130422 4

The intravenous (IV) and subcutaneous (SC) toxicity and absorption kinetics of the antileishmanial triterpene saponin PX-6518 and its active constituents maesabalide-III and -IV were studied in mice and dogs. A high-dose wash-out study of PX-6518 at 20 mg/kg SC for 5 days and a single low-dose wash-out study at 1, 2.5 or 5 mg/kg SC and IV with follow-up until day 35 after treatment were performed in mice. Beagle dogs received three escalating doses of maesabalide-III and -IV at weekly intervals ...[more]

PMID: 23609628

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Project description:BackgroundBuprenorphine is used for canine postoperative pain management. This study aimed to describe the pharmacokinetics and evaluate the analgesic efficacy of buprenorphine (Simbadol, 1.8?mg/mL) administered by different routes in dogs undergoing ovariohysterectomy. Twenty-four dogs were included in a randomized, prospective, masked, clinical trial. Buprenorphine (0.02?mg/kg) was administered intravenously (IV), intramuscularly (IM) or subcutaneously (SC) (n?=?8/group) 0.5?h before general anesthesia with propofol-isoflurane. Carprofen (4.4?mg/kg SC) was administered after anesthetic induction and before ovariohysterectomy. Pain was scored using the short-form Glasgow composite pain scale for dogs (SF-GCPS). Dogs were administered morphine (0.25?mg/kg IV) when SF-GCPS scores were???5/20. Blood sampling was performed up to 720?min after drug administration. Plasma buprenorphine and norbuprenorphine concentrations were analyzed using liquid chromatography mass spectrometry. Pharmacokinetics of buprenorphine was described using a non-compartmental model (PK Solver 2.0). Statistical analysis was performed using linear mixed models and Fisher's exact test (p?<?0.05).ResultsPain scores were significantly higher than baseline after IV (0.5-2?h), IM (0.5-3?h) and SC (0.5-4?h) but not among groups. Prevalence of rescue analgesia was significantly higher in SC (7/8 dogs) than IV (2/8) but not different between IV and IM (3/8) or IM and SC. The frequency of rescue analgesia was not significantly different among groups (IV?=?2, IM?=?5 and SC?=?9). Norbuprenorphine was not detected. For IV, IM and SC administration, clearance was 1.29, 1.65 and 1.40?L/hour/kg, volume of distribution was 6.8, 14.2 and 40.1?L/kg, the elimination half-life was 3.7, 5.7, 22?h, and the area under the plasma concentration-time curved extrapolated to infinity was 15.7, 12.4 and 16.4?ng/mL/hour, respectively. Bioavailability for IM and SC was 62.6 and 40%, respectively. Maximum plasma concentrations of buprenorphine were 6.2 and 1.3?ng/mL at 0.14 and 0.33?h after IM and SC administration, respectively.ConclusionsThe route of administration influences the analgesic efficacy of buprenorphine in dogs. SC administration of buprenorphine failed to provide clinical analgesia due to erratic drug absorption. At the doses administered, the IV and IM routes are preferred for postoperative analgesia.

Dataset Information

Intravenous and subcutaneous toxicity and absorption kinetics in mice and dogs of the antileishmanial triterpene saponin PX-6518.

Publications

Intravenous and subcutaneous toxicity and absorption kinetics in mice and dogs of the antileishmanial triterpene saponin PX-6518.

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