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Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

ABSTRACT: A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%.

SUBMITTER: Bernareggi A

PROVIDER: S-EPMC172143 | biostudies-other | 1988 Feb

REPOSITORIES: biostudies-other

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Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

Bernareggi A A Danese A A Cavenaghi L L

Antimicrobial agents and chemotherapy 19880201 2

A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbio ...[more]

PMID: 3364946

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Project description:Background and objectiveDexmedetomidine is a potent agonist of α2-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing.MethodsNon-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19-27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion.ResultsThe absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals.ConclusionsOur final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34.

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Dataset Information

Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

Publications

Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

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