Exploring Factors Causing Low Brain Penetration of the Opioid Peptide DAMGO through Experimental Methods and Modeling

Abstract

To advance the development of peptide analogues for improved treatment of pain, we need to learn more about the blood-brain barrier transport of these substances. A low penetration into the brain, with an unbound brain to blood ratio, Kp,uu, of 0.08, is an important reason for the lack of effect of the enkephalin analogue DAMGO (H-Tyr-d-Ala-Gly-MePhe-Gly-ol) according to earlier findings. The aim of this study was to investigate the role of efflux transporters, metabolism in the brain, and/or elimination through interstitial fluid bulk flow for the brain exposure of DAMGO. The in vivo brain distribution of DAMGO was evaluated using microdialysis in the rat. Data were analyzed with population modeling which resulted in a clearance into the brain of 1.1 and an efflux clearance 14 μL/min/g_brain. The efflux clearance was thus much higher than the bulk flow known from the literature. Coadministration with the efflux transporter inhibitors cyclosporin A and elacridar in vivo did not affect Kp,uu. The permeability of DAMGO in the Caco-2 assay was very low, of the same size as mannitol. The efflux ratio was <2 and not influenced by cyclosporin A or elacridar. These results indicate that the well-known efflux transporters Pgp and Bcrp are not responsible for the higher efflux of DAMGO, which opens up for an important role of other transporters at the BBB.

Revisiting atenolol as a low passive permeability marker

“…For the microdialysis study, vessel catheters and microdialysis probes were implanted in rats as previously described [ 13 , 16 ]. Briefly, the rats were anesthetized using 2.5% isoflurane and their body temperature were maintained at 37 °C using CMA/150 temperature controller (CMA, Stockholm, Sweden) throughout the surgery.…”

“…The previously developed integrated plasma-brain pharmacokinetic model for oxymorphone, oxycodone, and DAMGO was used in this study, with modification based on the data from the microdialysis study of S-atenolol [ 13 , 19 , 20 ]. All observed data of S-atenolol were included in the model comprising total plasma concentration in arterial sampling, unbound concentration in venous plasma from microdialysis sampling in jugular vein, and unbound concentration in brain ECF from microdialysis sampling in right striatum (Fig.…”

“…Moreover, CL out may be affected by metabolism and ECF bulk flow [ 12 ]. The ratio of CL in over CL out values, is equal to the unbound equilibrium partition coefficient, K p,uu,brain , which is defined as the ratio of unbound drug concentration in brain ECF to that in plasma at the steady state [ 13 ]. Even when steady state concentrations are not achieved, but with rate processes following first order kinetics (i.e.…”

Understanding the Blood‐Brain Barrier and Beyond: Challenges and Opportunities for Novel CNS Therapeutics

“…78 A number of animal studies using microdialysis for time-course information on unbound drug in plasma and brain provide such mechanistic information. [78][79][80][81][82][83][84] Overall, these studies show that brain distribution of a drug administered as liposomal formulation depends on both drug properties and liposomal formulation characteristics (Table 2). It may indeed enhance BBB drug delivery for drugs that have limited BBB transport, such as methotrexate and DAMGO, but may also counteract active uptake, as is the case for diphenhydramine (Table 2) and quetiapine, where the latter used lipid core nanocapsules.…”

“…Whereas providing interesting data, such studies have room for improvement to provide sufficient mechanistic insight 78 . A number of animal studies using microdialysis for time‐course information on unbound drug in plasma and brain provide such mechanistic information 78–84 …”