Evidence of pulmonary tropism of bamifylline and its main active metabolite
P Schiantarelli1, D Acerbi, G C Botta
1Research Division, Chiesi Farmaceutical S.p.A., Parma, Italy.
Abstract:
The extent of the extraplasmatic tropism of bamifylline (Bamifix) was evaluated in the rat and in man by assaying concentrations of bamifylline and of its main active metabolite AC-119 in lung tissue and plasma. After a single oral and intravenous administration of bamifylline in the rat, the ratio between pulmonary and plasma concentrations was between 2.0 and 3.2 for bamifylline, and between 4 and 15 for AC-119 during the observation period considered. On the other hand, the same ratios, calculated after the oral and intravenous administration of theophylline, ranged between 0.20 and 0.39. In studies on man, samples of plasma and lung tissue were obtained during surgery in subjects affected by pulmonary neoplasia and previously subjected to therapy with bamifylline according to the usual dosage scheme. The ratios between tissue and plasma concentrations, at the steady-state and in conditions of equilibrium between the compartments, were 9.4 for bamifylline and 34.7 for its active metabolite. The particular tissue tropism of bamifylline, that appears to be due to its high lipophilic character, could partly explain its high therapeutic index.
Insights
Bamifylline (Bamifix) shows significant lung tissue tropism in rats and humans, concentrating higher than theophylline. This enhanced drug accumulation in lung tissue may contribute to its favorable therapeutic index.
Area of Science:
- Pharmacology
- Drug Metabolism and Pharmacokinetics
- Pulmonary Medicine
Background:
- Bamifylline (Bamifix) is a drug used for respiratory conditions.
- Understanding drug distribution in tissues is crucial for optimizing therapeutic efficacy.
- Extraplamatic tropism, or drug accumulation in tissues outside the bloodstream, can influence a drug's safety and effectiveness.
Purpose of the Study:
- To evaluate the extraplamatic tropism of bamifylline and its active metabolite AC-119 in lung tissue compared to plasma.
- To compare the tissue-to-plasma concentration ratios of bamifylline with those of theophylline.
- To investigate the potential relationship between bamifylline's lipophilicity and its therapeutic index.
Main Methods:
- Administered bamifylline orally and intravenously to rats, measuring drug and metabolite concentrations in lung tissue and plasma.
- Administered theophylline orally and intravenously to rats, measuring drug concentrations in lung tissue and plasma for comparison.
- Obtained plasma and lung tissue samples from human patients undergoing surgery who had received bamifylline therapy, measuring drug and metabolite concentrations at steady-state.
Main Results:
- In rats, bamifylline and its metabolite AC-119 showed significantly higher concentrations in lung tissue compared to plasma (ratios 2.0-3.2 for bamifylline, 4-15 for AC-119).
- Theophylline exhibited lower lung tissue-to-plasma concentration ratios (0.20-0.39) in rats.
- In humans, steady-state ratios of bamifylline and AC-119 in lung tissue to plasma were substantial (9.4 for bamifylline, 34.7 for AC-119).
Conclusions:
- Bamifylline demonstrates marked tropism for lung tissue in both rats and humans.
- The high lipophilic character of bamifylline is suggested as a factor contributing to its enhanced tissue distribution.
- The observed lung tissue tropism of bamifylline may partly explain its high therapeutic index, warranting further clinical investigation.
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