Evaluation of antitubercular drug insertion into preformed dipalmitoylphosphatidylcholine monolayers

Insertion profiles of antitubercular drugs isoniazid (INH), rifampicin (RFM) and ethambutol (ETH) into dipalmitoylphosphatidylcholine (DPPC) membrane models were evaluated by Langmuir monolayer technique. Maximum drug insertion into DPPC monolayer was observed with rifampicin with a surface pressure increase (Δπmax) in the range of 21-33 mN/m depending upon rifampicin concentration. Isoniazid had minimal insertion resulting in a lower Δπmax of about 2-3 mN/m, suggestive of minimal interactions between INH and DPPC. Ethambutol surface pressure increment on insertion resulted in an intermediate rise in the Δπmax (6-10 mN/m). Antitubercular drug combination in the ratio of 2 mM:0.7 mM:4.5 mM for INH:RFM:ETH, attained Δπmax between 25 and 33 mN/m. Insertion profiles similar to rifampicin were exhibited by the antitubercular drug mixture suggestive of predominant rifampicin insertion into the DPPC monolayer. The extent of drug insertion into the DPPC monolayer is suggestive of the drug penetration potential into biological membranes in vivo. Higher RFM Δπmax is suggestive of excellent cell membrane penetration, which explains broad reach of the drug to all the organs including the cerebrospinal fluid while lower Δπmax of INH suggests poor membrane penetration restricting the entry of the drug in different biological membranes. DPPC membrane destabilization was observed at higher antitubercular drug concentrations indicated by the negative slopes of the surface pressure-time curves. This may correlate with the dose related toxic effects observed in tuberculosis affected patients. Drug insertion studies offer a potential tool in understanding the pharmacotoxicological behavior of the various pharmacological agents.