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Most studies of blood-brain barrier (BBB) permeability and transport are conducted at a single pH , but more detailed information can be revealed by using multiple pH values. A pH -dependent biophysical model was applied to the mechanistic analysis of published pH -dependent BBB luminal uptake data from three opioid derivatives in rat: pentazocine (Suzuki et al., 2002a, 2002b), naloxone (Suzuki et al., 2010a), and oxycodone (Okura et al., 2008). Two types of data were processed: in situ brain perfusion (ISBP) and brain uptake index (BUI). The published perfusion data were converted to apparent luminal permeability values, P app , and analyzed by the p CEL-X program (Yusof et al., 2014), using the pH -dependent Crone-Renkin equation ( pH -CRE) to determine the impact of cerebrovascular flow on the Michaelis-Menten transport parameters (Avdeef and Sun, 2011). For oxycodone, the ISBP data had been measured at pH 7.4 and 8.4. The present analysis indicates a 7-fold lower value of the cerebrovascular flow velocity, F pf , than that expected in the original study. From the pyrilamine-inhibited data, the flow-corrected passive intrinsic permeability value was determined to be P 0 = 398 × 10 − 6 cm·s − 1 . The uptake data indicate that the neutral form of oxycodone is affected by a transporter at pH 8.4. The extent of the cation uptake was less certain from the available data. For pentazocine, the brain uptake by the BUI method had been measured at pH 5.5, 6.5, and 7.4, in a concentration range 0.1–40 mM. Under similar conditions, ISBP data were also available. The pH -CRE determined values of F pf from both methods were nearly the same, and were smaller than the expected value in the original publication. The transport of the cationic pentazocine was not fully saturated at pH 5.5 at 40 mM. The transport of the neutral species at pH 7.4 appeared to reach saturation at 40 mM pentazocine concentration, but not at 12 mM. In the case of naloxone, a pH -dependent Michaelis-Menten equation ( pH -MME) analysis of the data indicated a smooth sigmoidal transition from a higher capacity uptake process affecting cationic naloxone (pH 5.0–7.0) to a lower capacity uptake process affecting the neutral drug (pH 8.0–8.5), with cross-over point near pH 7.4. Evidently, measurements at multiple pH values can reveal important information about both cerebrovascular flow and BBB transport kinetics. [ABSTRACT FROM AUTHOR]

Purpose: To determine the flow-corrected luminal permeability, P, of lipophilic drugs measured by the in situ brain perfusion method under circumstances where the traditional Crone-Renkin equation (CRE) method, using diazepam as a flow marker, often fails. Methods: The pH-dependent rate of brain penetration of five lipophilic drugs (amitriptyline, atomoxetine, imipramine, indomethacin, maprotiline, sertraline), as well as of atenolol and antipyrine, were measured in Sprague-Dawley rats. A new pH-dependent CRE was derived and applied to remove the hydrodynamic component of effective permeability, P, to produce P values. Results: It was shown by the analysis of the in situ data in the pH 6.5-8.5 interval for the lipophilic bases that the average vascular flow F = 0.036 mL∙g∙s, centered in a 'flow-limit window' (FLW) bounded by P = 170 and P = 776 (10 cm∙s units). It was shown that the traditional CRE is expected not to work for half of the molecules in the FLW and is expected to underestimate (up to 64-fold) the other half of the molecules. Conclusion: The new pH-CRE flow correction method applied to lipophilic ionizable drugs, based on the pH partition hypothesis, can overcome the limitations of the traditional CRE. [ABSTRACT FROM AUTHOR]

Purpose: To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). Methods: Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor. Results: The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the 'leave-many-out' procedure, with q = 0.92 ± 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability. Conclusion: BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability. [ABSTRACT FROM AUTHOR]