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Pharmacokinetics of anthracene-9-carboxylic acid, a potent myotonia-inducer
Abstract:
The pharmacokinetics of anthracene-9-carboxylic acid (9-AC), a potent myotonia-inducer, was determined in 9 New Zealand White male rabbits after the intravenous injection of 36 microM X kg-1. Myotonic contractions appeared 30 to 80 sec after the beginning of injection. One minute after injection, 25% of the administered dose remains in the blood (9-AC in plasma + 9-AC in cells). Of the 9-AC present in whole blood, 78% is in plasma and can be totally extracted with chloroform whereas the remaining 22% is in the blood cells and can not be extracted. The disappearance of 9-AC from plasma can be explained numerically by assuming an open two-compartment model. By means of a non-linear regression analysis the equation Cp = 20.65e-0.3216t + 28.35e-0.0147t was obtained. This equation gives the best fir for the mean values of all the experiments. The equilibrium between the two compartments is reached in 9.0 min and the Vdss X kg-1 at this time is equal to 273 +/- 18.6 ml X kg-1 which is only marginally larger (10%) than the estimated extracellular volume (246.0 ml X kg-1), suggesting that 9-AC barely penetrates into the cells. The plasma concentration values at t1/2e1 and 3t1/2e1 are 1.07 X 10(-4) M and 2.69 X 10(-5) M, respectively. Similar concentration values were found by other authors as capable of reducing the chloride conductance of skeletal muscle membrane and producing myotonia in vivo and in vitro. Thus, there is a good correspondence between the concentrations active in vitro and the concentrations of plasma in vivo found in this study. Other pharmacokinetic parameters are: t1/2 alpha = 2.8 +/- 0.3 min; t1/2 beta = 45.7 +/- 2.2 min; Area under the curve (AUC) = 1920 +/- 125.0 micrograms X min X ml-1; K12 = 0.085 +/- 0.01 min-1; K21 = 0.162 +/- 0.02 min-1; t1/2e1 = 28.84 +/- 2.2 min., and V1 X kg-1 = 172.1 +/- 9.7 ml. All our findings plus the rapid appearance of myotonic signs and the correspondence with the in vitro studies support the previous assertion that 9-AC acts on the cellular membrane of the skeletal muscles.
Insights
This study determined the pharmacokinetics of anthracene-9-carboxylic acid (9-AC) in rabbits, finding it induces myotonia by acting on skeletal muscle membranes. The drug
Area of Science:
- Pharmacology
- Pharmacokinetics
- Muscle Physiology
Background:
- Anthracene-9-carboxylic acid (9-AC) is a known myotonia inducer.
- Understanding its pharmacokinetic profile is crucial for its therapeutic or toxicological assessment.
Purpose of the Study:
- To determine the pharmacokinetics of anthracene-9-carboxylic acid (9-AC) following intravenous administration in rabbits.
- To correlate in vivo plasma concentrations with in vitro myotonia-inducing effects.
Main Methods:
- Intravenous injection of 36 µM/kg 9-AC into male New Zealand White rabbits.
- Blood sampling and analysis of 9-AC concentration in plasma and erythrocytes.
- Mathematical modeling using a two-compartment open model and non-linear regression analysis.
Main Results:
- Myotonic contractions observed within 30-80 seconds post-injection.
- 9-AC primarily distributes in plasma (78%) with limited cell penetration.
- Plasma concentration decay described by Cp = 20.65e-0.3216t + 28.35e-0.0147t, with a half-life of approximately 45.7 minutes.
- Achieved plasma concentrations align with those known to reduce skeletal muscle chloride conductance.
Conclusions:
- 9-AC exhibits limited distribution into cells, primarily remaining in the plasma.
- The in vivo plasma concentrations of 9-AC correlate well with in vitro data demonstrating myotonia induction.
- Findings support the hypothesis that 9-AC exerts its myotonia-inducing effects directly on skeletal muscle cell membranes.