pH-dependent interaction of psychotropic drug with glycerophospholipid monolayers studied by the Langmuir technique.
We have earlier investigated the interaction of the antipsychotic drugs chlorpromazine(CPZ) and olanzapine(OLP) with glycerophospholipid monolayers. These experiments were carried out at high and low temperatures and showed that OLP had a more pronounced effect on the packing of the phospholipid (PL) monolayers than CPZ. At pH 7.36, where OLP consists of one positive and one neutral species. In the present work we have studied the interaction of the drugs with monolayers of PLs by the Langmuir technique at pH 6.00 and 10.00 at 37°C. The PLs were palmitoylphosphatidyl-choline(DPPC), 1-stearoyl-2-arachinodonoylphoshatidylcholine(SAPC),dipalmitoylphosphatidyl-serine(DPPS) and 1-palmitoyl-2-oleoylphosphatidylserine(POPS). OLP has a pKa around 7.4, with one neutral and one positive species at pH 6.00 and pH 10.00, respectively. CPZ has pKa value around 9.4, and is positively charged at pH 6.00 and neutral at pH 10.00. Our studies revealed that the surface area of DPPC with CPZ in the subphase did not change at pH 6.00. In contrast, OLP increased the mean molecular area(MMA) of DPPC at pH 6.00, while CPZ caused distinct increase in MMA on the monolayer packing of all the other PLs, including monolayers of DPPC at pH 10.00. OLP, increased MMA of all PLs at both pHs. Further, OLP increased MMA of DPPC (pH 10.00), SAPC (pH 10.00), DPPS (pH 6.00) and POPS (pH 6.00) at 30mN/m, the expected MMA of biological membranes. CPZ had the more pronounced effect at lift-off and gave an effect of the monolayers with negatively charged head groups in accordance our earlier experiments. However, CPZ affected the packing of the SAPC monolayer both at pH 6.00 and 10.00, and DPPC at pH 10.00. Both these PLs have neutral choline head group. Our results suggest that both drugs intercalate in the PL monolayers, and that the intercalation might involve electrostatic interaction with the head groups or hydrophobic interaction with the acyl chains of the PLs, or both. Probably the drugs intercalate to different extents depending on charge of both the drugs and the PL head groups. Our investigation may suggest that the interaction of CPZ and OLP with membrane PLs could be linked to both the psychotropic and the side effects.
Steinkopf
Signe
S
Department of Biomedical Laboratory Science, Bergen University College, Bergen, Norway. signe.steinkopf@hib.no
Simeunović
Aida
A
Bustad
Helene J
HJ
Ngo
Thi Ha
TH
Sveaass
Hege
H
Gjerde
Anja U
AU
Holmsen
Holm
H
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D001569:Benzodiazepines / Q000737:chemistry; D002746:Chlorpromazine / Q000737:chemistry; D020404:Glycerophospholipids / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D000077152:Olanzapine; D010713:Phosphatidylcholines / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D011619:Psychotropic Drugs / Q000737:chemistry*; D013696:Temperature
C462319:1-strearoyl-2-arachidonyl-sn-glycero-3-phosphatidylcholine; D020404:Glycerophospholipids; D010713:Phosphatidylcholines; D010718:Phosphatidylserines; D011619:Psychotropic Drugs; D001569:Benzodiazepines; D015060:1,2-Dipalmitoylphosphatidylcholine; C038694:dipalmitoylphosphatidylserine; C050294:1-palmitoyl-2-oleoylglycero-3-phosphoserine; D000077152:Olanzapine; D002746:Chlorpromazine