Pharmacokinetic Considerations of Nanodelivery to the Brain: Using Modeling and Simulations to Predict Outcome of Liposomal Formulations

Lindqvist, Annika,1983-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Translational PKPD (författare)

Pharmacokinetic Considerations of Nanodelivery to the Brain : Using Modeling and Simulations to Predict Outcome of Liposomal Formulations

The use of nanocarriers is an intriguing solution to increase the brain delivery of novel therapeutics. The aim of this paper was to use pharmacokinetic analysis and simulations to identify key factors that determine the effective drug concentration-time profile at the target site in the brain. Model building and simulations were based on experimental data obtained from the administration of the opioid peptide DAMGO in glutathione tagged PEGylated liposomes to rats. Different pharmacokinetic models were investigated to explore the mechanisms of increased brain delivery. Concentration time profiles for a set of formulations with varying compound and carrier characteristics were simulated. By controlling the release rate from the liposome, the time profile and the extent of brain delivery can be regulated. The modeling did not support a mechanism of the liposomes passing the brain endothelial cell membrane in an intact form through endocytosis or transcytosis. The most likely process was found to be fusion of the liposome with the endothelial luminal membrane. The simulations revealed that low permeable compounds, independent on efflux, will gain the most from a nanocarrier formulation. The present model based approach is useful to explore and predict possibilities and limitations of carrier-based systems to the brain.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmaceutiska vetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmaceutical Sciences hsv//eng
Liposomes
Nanocarriers
Brain delivery
Pharmacokinetics
Active transport
Blood-brain barrier
Permeability
Release rate
Modeling and simulations
Farmakokinetik och läkemedelsterapi
Pharmacokinetics and Drug Therapy

Fridén, MarkusAstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden(Swepub:uu)mafri535 (författare)
Hammarlund-Udenaes, MargaretaUppsala universitet,Institutionen för farmaceutisk biovetenskap,Translational PKPD(Swepub:uu)marghamm (författare)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

Ingår i:European Journal of Pharmaceutical Sciences: Elsevier BV92, s. 173-1820928-09871879-0720

Av författaren/redakt...: Lindqvist, Annik ...; Fridén, Markus; Hammarlund-Udena ...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Farmaceutiska ve ...

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