Derivative spectrophotometry as a tool for the determination of drug partition coefficients in water/dimyristoyl-L-alpha-phosphatidylglycerol (DMPG) liposomes.
The partition coefficients (K(p)) between lipid bilayers of dimyristoyl-L-alpha-phosphatidylglycerol (DMPG) unilamellar liposomes and water were determined using derivative spectrophotometry for chlordiazepoxide (benzodiazepine), isoniazid and rifampicin (tuberculostatic drugs) and dibucaine (local anaesthetic). A comparison of the K(p) values in water/DMPG with those in water/DMPC (dimyristoyl-L-alpha-phosphatidylcholine) revealed that for chlordiazepoxide and isoniazid, neutral drugs at physiological pH, the partition coefficients are similar in anionic (DMPG) and zwitterionic (DMPC) liposomes. However, for ionised drugs at physiological pH, the electrostatic interactions are different with DMPG and DMPC, with the cationic dibucaine having a stronger interaction with DMPG, and the anionic rifampicin having a much larger K(p) in zwitterionic DMPC. These results show that liposomes are a better model membrane than an isotropic two-phase solvent system, such as water-octanol, to predict drug-membrane partition coefficients, as they mimic better the hydrophobic part and the outer polar charged surface of the phospholipids of natural membranes.
Rodrigues
C
C
CEQUP/Departamento de Química, Faculdade de Ciências, Universidade do Porto, R. Campo Alegre, 4169-007 Porto, Portugal.
Gameiro
P
P
Reis
S
S
Lima
J L
JL
de Castro
B
B
D002707:Chlordiazepoxide / Q000737:chemistry*; D003992:Dibucaine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007538:Isoniazid / Q000737:chemistry*; D008051:Lipid Bilayers; D010715:Phosphatidylglycerols; D012293:Rifampin / Q000737:chemistry*; D013053:Spectrophotometry / Q000379:methods*; D055672:Static Electricity
D008051:Lipid Bilayers; D010715:Phosphatidylglycerols; D002707:Chlordiazepoxide; C002773:dimyristoylphosphatidylglycerol; D003992:Dibucaine; D007538:Isoniazid; D012293:Rifampin