Armodafinil’in membran lipidleri etkileşiminin DPPC model membran sistemi ile araştırılması

Year 2019, Volume: 76 Issue: 1, 41 - 52, 01.03.2019

Handan Kırkoçoğlu Sevgi Türker Kaya

Abstract

Amaç: Modafinilin rasemik bileşiğinin R-enantiyomeri olan Armodafinil ARM tam olarak bilinmeyen hücresel etki mekanizması ile uyku bozukluklarında kullanılan merkezi sinir sistemi MSS uyarıcı ve uyanıklığı arttırıcı bir ajandır. Her ne kadar ARM’nin uyku/uyanıklık düzenini etkileyen enzimlere ve reseptörlere bağlanmadığı ve vücutta çok iyi dağıldığı gösterilse de, bildiğimiz kadarıyla onun MSS’deki etkinliğini değerlendiren bir çalışma bulunmamaktadır. Bir ilacın lipid çözünürlüğünün onun MSS erişilebilirliğini direkt olarak etkilediği göz önünde bulundurulduğunda ARM’nin lipidlerin içine nasıl nüfuz ettiği ve onlarla ne tarz etkileşmelere girdiğinin araştırılması bu konuya faydalı katkılar sağlayabilir. Bu bağlamda, bu çalışmada dipalmitoilfosfatidilkolin DPPC multilamellar veziküler MLVs adlı basitleştirilmiş model membran sistemi ile ARM’in konsantrasyona bağlı etkileşmeleri araştırıldı.Yöntem: ARM’nin DPPC MLV’lerinin ana geçiş sıcaklığı Tm , entalpi ΔH , kooperatiflik birimi CU ve CH2 asimetrik, C = O simetrik ve PO2- asimetrik frekans değerleri üzerine etkileri konsantrasyona bağlı % 1-1020 mol olarak diferansiyel tarama kalorimetresi DSC ve fourier dönüşümü infrared FT-IR spektroskopisi kullanılarak incelendi. Results: All data showed that with the addition of ARM at all concentrations into pure DPPC MLVs, decreased lipid order acyl chain flexibility , but increased lipid dynamics fluidity , glycerol backbone and hydrogen bonding capacity head groups of lipids in the gel and liquid crystalline phases. Moreover, it also caused to shift Tm, ΔH and CU to lower values. Conclusion: The corresponding findings revealed that ARM has high affinity for binding to acyl chains and hydrophilic parts of phosphatidylcholine lipids. This was also supported by the obtained differences in the thermotropic properties of lipids caused by ARM. The high tendency of ARM to interact with lipids may also mean that it may also lead to perturb the packing of membrane lipids. The results provides incorporation profile of ARM into biological membranes depending on concentration, which may further contribute to new drug development against sleep disorders and related diseases. Bulgular: Elde edilen tüm verilere göre saf DPPC MLV’lerine ARM eklenmesiyle, lipit düzeninde açil zincir esnekliği azalmaya karşılık lipid dinamiği akışkanlık , gliserol omurgası ve lipid kafa gruplarının hidrojen bağlama kapasitelerinde sıvı ve kristal fazda artma olduğu tespit edildi. Ayrıca, Tm, ΔH ve CU parametrelerinin de daha düşük değerlere kaydığı bulundu.Sonuç: Tüm bulgular, ARM’nin, fosfatidilkolin lipidlerinin açil zincirlerine ve hidrofilik kısımlarına bağlanmak üzere yüksek afinite gösterdiğini ortaya koydu. Bu durum ARM’nin lipidlerin termotrofik parametrelerinde neden olduğu farklılıklarla da desteklendi. ARM’nin lipidlerle yüksek oranda etkileşime girme eğilimi onun membran lipidlerinin paketlenmesini bozmasına da neden olabileceği anlamına gelebilir. Elde edilen tüm sonuçlar ARM’nin biyolojik membranlar ile ne tarz etkileşmelere girdiği ile ilgili bilgiler sunmakla birlikte uyku düzensizlikleri ve ilgili hastalıklara karşı yeni ilaç geliştirme çalışmalarına katkı sağlayabilir

Keywords

Darmodafinil, FT-IR, DSC, ilaçlipid etkileşmeleri, dipalmitoilfosfatidilkolin

The investigation of the interaction of Armodafinil with membrane lipids by using DPPC model membrane system

Abstract

Objective: Armodafinil ARM , the R-enantiomer of the racemic compound of modafinil, is a central nervous system CNS stimulant and wakefulness-promoting used in sleep disorders with unknown exact cellular mechanism. Although it was shown that it does not binds to enzymes and receptors that regulate sleep/wake regulation as well as it is very-well distributed in the body, there is no report evaluating its CNS availability to the best of our knowledge. Considering that lipid solubility of a drug directly affects CNS accessibility, the investigation of ARM how to penetrate into and to interact with lipids would be beneficial to contribute to such issue. Related with this, the interaction of ARM with simplified model membrane system named dipalmitoylphosphatidylcholine DPPC multilamellar vesicles MLVs depending on concentrations was investigated in the present study.Methods: The effects of ARM as a function of concentration 1-10-20 mol % on main transition temperature Tm , enthalpy ΔH , cooperativity unit CU and frequency values of CH2 asymmetric, C=O symmetric and PO2- asymmetric stretching of DPPC MLVs were studied by utilizing differential scanning calorimetry DSC and fourier transform infrared FT-IR spectroscopy

Keywords

Darmodafinil, FT-IR spectroscopy, DSC, drug-lipid interaction, dipalmitoylphosphatidylcholines

References

• 1. Ballas C, Dinges DF. Stimulant and wake-promoting substances. Encyclop Neurosci, 2009; 1: 419-24.
• 2. Wang Z, Liu JF. The molecular basis of imsonia: implication for therapeutic approaches. Drug Dev Res, 2016; 77: 427-36.
• 3. Harsh JR, Hayduk R, Rosenberg R. The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin, 2006; 22: 761–74.
• 4. Czeisler CA, Walsh JK, Wesnes KA. Armodafinil for treatment of excessive sleepiness associated with shift work disorder: a randomized controlled study. Mayo Clin Proc, 2009; 84: 958–72.
• 5. Peetla C, Stine A, Labhasetwar V. Biophysical interactions with model lipid membranes: applications in drug discovery and drug delivery. Mol Pharmaceutics, 2009; 6: 1264–76.
• 6. Shrestha H, Bala R, Arora S. Lipid-based drug delivery systems. J Pharmaceutics, 2014; 801820: 1-10.
• 7. Turker S, Wassall S, Stillwell W, Severcan F. Convulsant agent pentylenetetrazol does not alter the structural and dynamical properties of dipalmitoylphosphatidylcholine model membranes. J Pharma Biomed Anal, 2011; 54: 379-386.
• 8. Ezer N, Sahin I, Kazanci N. Alliin interacts with DMPC model membranes to modify the membrane dynamics: FTIR and DSC Studies. Vib Spect, 2017; 89: 1-8.
• 9. Sahin I, Bilge D, Kazanci N, Severcan F. Concentration dependent effect of melatonin on DSPC membrane. J Mol Struc, 2013; 1052: 183-8.
• 10. Shrestha H, Bala R, Arora S. Lipid-based drug delivery systems. J Pharmaceu, 2014; 801820: 1-10.
• 11. Barroso R, Basso G, Costa-Filho A. Interactions of the antimalarial amodiaquine with lipid model membranes. Chem Phys Lipid, 2015; 186: 68-78.
• 12. Darwish M, Kirby M, Hellriegel ET, Robertson P. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig, 2009; 29: 613–23.
• 13. Nuvigil. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2013.
• 14. Boltz JR, Feigenson GW. A novel strategy for the preparation of liposomes: rapid solvent exchange. BBA, 1999; 1417: 232-45.
• 15. Liossi A, Ntountaniootis D, Becker-Baldus J. Exploring the interactions of irbesartan and irbesartan-2-hydroxylpropyl-beta-cyclodextrin complex with model membranes. BBA-Biomemb, 2017; 1862: 1089-98.
• 16. Jagalski V, Barker R, Topgaard D, Cardenas M. Biophysical study of resin acid effects on phospholipid membrane structure and properties. BBA-Biomemb, 2016; 1858: 2827-38.
• 17. Augustynska D, Burda K, Jemiola-Rzeminska M. Temperature-dependent bifurcation of cooperative interactions in pure and enriched in beta-carotene DPPC liposomes. Chemico-Biol Int, 2016; 256: 236- 48.
• 18. Sekowski S, Ionov M, Dubis A, Mavlyanov S, Bryszewska M. Biomolecular interactions of tannins isolated from Oenothera gigas with liposomes. J Memb Biol, 2016; 249: 171-9.
• 19. Altunuyar C, Sahin I, Kazanci N. A comparative study of the effects of cholesterol and desmosterol on DPPC model membranes. Chem Phys Lipid, 2015; 188: 37-45.
• 20. Korkmaz F, Severcan F. Effect of progesterone on DPPC membrane: evidence for lateral phase separation and inverse action in lipid dynamics, Arch Biochem Biophys. 2005;440(2):141-7.
• 21. Türker-Kaya S, Kına A, Alın S. Divergent interaction profiles of gabapentin and levetiracetam with dipalmitoylphosphatidylcholine lipids, Int J Epi, 2017; 4: 150-8.
• 22. Engelke M, Jessel R, Wiechmann A, Diehl H. Effect of inhalation anesthetic on the phase behavior, permeability and order of phosphatidylcholine bilayers. Biophys Chem, 1997; 67: 127-38.
• 23. Brandenburg K, Seydel U. Investigation into the fluidity of lipopolysaccharide and free lipid A membrane systems by Fourier-transform infrared spectroscopy and differential scanning calorimetry. European J Biochem, 1990; 191: 229-36.
• 24. https://pubchem.ncbi.nlm.nih.gov/compound/ Armodafinil#section=Top (accessed on 20.06.2017).
• 25. Nogueira AOD, de Sousa RS, Pereira LS, Mallmann C, Ferreira AD, Clementin RM, de Lima VR. Physicochemical interactions among alphaeleostearic acid-loaded liposomes applied to the development of drug delivery systems. J Mol Str, 2018;1154:248-255.
• 26. Silva LAD, Cintra ER, Alonso ECP, Alves GL, Lima EM, Taveira SF, da Cunha MSS, Marreto RN, Selection of excipients for the development of carvedilol loaded lipid-based drug delivery systems. J Therm Anal Cal, 2017; 130 :1593-1604.
• 27. Potamitis C, Chatzigeorgiou P, Siapi E, Viras K, Mavromoustakos T, Hodzic A, et al. Interactions of the AT1 antagonist valsartan with dipalmitoyl– phosphatidylcholine bilayers. BBA-Biomemb, 2011; 1808: 1753–63.
• 28. Kato N, Ishijima A, Inaba T, Nomura F, Takeda S. Effects of lipid composition and solution conditions on the mechanical properties of membrane vesicles. Memb. (Basel), 2015; 5: 22-47.
• 29. Tresset G, The multiple faces of self-assembled lipidic systems, PMC Biophy, 2009; 2(3):1-6.
• 30. S. Tristram-Nagle. Use of X-ray and neutron scattering methods with volume measurements to determine lipid bilayer structure and number of water molecules/lipid. In E. A. Disalvo Ed. Membrane hydration: The role of water in the structure and function of biological membranes (Subcellular biochemistry) (Springer, 2015) pp 17- 43.
• 31. Heimburg T. A model for the lipid pretransition: coupling of ripple formation with the chain-melting transition. Biophys J, 2000; 78: 1154-65.
• 32. Lombardi D, Cuenoud B, Kramer SD. Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties? European J Pharmaceu Sci, 2009; 38: 533–47.
• 33. Nicolle LE, Zhanel GG, Harding GK. Microbiological outcomes in women with diabetes and untreated asymptomatic bacteriuria. World J Urol, 2006; 24(1): 61–5.
• 34. Harding GK, Zhanel GG, Nicolle LE, Cheang M. Manitoba Diabetes Urinary Tract Infection Study Group. Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med, 2002; 347(20):1576–83.
• 35. Schwartz J, Thomas R, Drake C. Armodafinil in the treatment of sleep/wake disorders. Neuropsychiatric Dis Treat, 2010; 6: 417-27.
• 36. Yeagle PL. The structure of Biological Membrane, 3 rd. ed. New York: CRC Press; 2011.
• 37. Moore DJ, Sills RH, Mendelsohn R. Peroxidation of erythrocytes: FTIR spectroscopy studies of extracted lipids, isolated membranes, and intact cells. Biospectra J, 1995; 1: 133–40.
• 38. Turker S, Severcan M, Ilbay G, Severcan F. Epileptic seizures induce structural and functional alterations on brain tissue membranes. BBA-Biomemb, 2014; 1838: 3088-96.