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Influence of time to achieve substrate distribution equilibrium between brain tissue and blood on quantitation of the blood-brain barrier P-glycoprotein effect

, : Influence of time to achieve substrate distribution equilibrium between brain tissue and blood on quantitation of the blood-brain barrier P-glycoprotein effect. Brain Research 1426: 1-17

Active efflux transport processes at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp)-mediated efflux, can limit brain uptake of therapeutics. Accurate determination of the consequent impact on brain uptake is assumed to require sampling post-attainment of brain-to-blood distribution equilibrium. Because this approach is not always feasible, understanding the relationship between apparent degree of efflux (e.g., calculated BBB P-gp effect) and the fraction of time remaining until distribution equilibrium is achieved (FTDE) would be advantageous. This study employed simulation strategies to explore this relationship in the simplest relevant system (absence of protein binding, saturable uptake, or metabolism at the BBB). Concentration-time profiles were simulated with a 4-compartment system (blood, peripheral tissues, BBB endothelium and brain parenchyma). A unidirectional endothelium-to-blood rate constant, PS(e), represented P-gp-mediated efflux. A parameter space was selected to simulate an 18-fold P-gp effect, (K(p,brain) at distribution equilibrium in the absence [K(p,brain)=82] vs. presence [K(p,brain)=4.5] of P-gp-mediated flux), as observed for paclitaxel in P-gp-deficient vs. P-gp-competent mice. Hypothetical compounds with different P-gp effects, peripheral compartment distribution kinetics, or times to achieve distribution equilibrium were simulated by perturbing the values of relevant model parameters. P-gp effects calculated prior to attainment of distribution equilibrium may be substantially erroneous. However, reasonably accurate estimates can be obtained relatively early in the net distributional phase (under 20% error at FTDE>0.36 or 0.11 for bolus or infusion administration, respectively). Potential errors associated with non-equilibrium calculations are dependent on both P-gp-mediated and P-gp-independent components of flux across the BBB.


PMID: 22036081

DOI: 10.1016/j.brainres.2011.10.009

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Man, R.Y.K.; Ting, L.K.F.; Fan, S.; Lau, M.M.H.; Siow, Y.L.; Chung, Y.H.; O.K.rmin, 2001: Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women. Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine lev...

Weicht, D.C.; Venn, C.; Hallen, C.P., 2012: Influence of the Oneida #3 mine tunnel drainage on Little Tomhicken Creek before and after the repair of an AMD passive treatment system. Drainage from the Oneida #3 mine tunnel, in the Eastern Middle anthracite field of eastern Pennsylvania, discharges into Little Tomhicken Creek near Hazleton, PA. The second largest discharge in the Catawissa Creek Watershed, this discharge has hi...

Stamenković, M.; Kohot, J.; Kuljanac, I., 1985: The Klippel-Trenaunay-Weber syndrome without nevi. Medicinski Arhiv 39(1): 29-31

Wan, P.J.; Hurley, T.W.; Guy, J.D.; Berner, D.L., 1997: Comparison of visual and automated colorimeters: An international collaborative study. Color as a fundamental quality of edible oils has been determined primarily by visual comparison methods for many decades. The automatic colorimeters introduced recently made it possible to replace the manually operated visual color instrument, wh...

Jahn A.F.; Davies D.G., 1992: A clinical approach to the professional voice. Blitzer, A , M F Brin, C T Sasaki, S Fahn And K S Harris Neurologic Disorders Of The Larynx Xxi+294p Thieme Medical Publishers, Inc : New York, New York, Usa; Georg Thieme Verlag: Stuttgart, Germany Illus 149-161

Wagner H.; Wessels F.; Zierden E.; Oberwittler W.; Losse H., 1972: Insulin secretion and glucose tolerance in animal experimental hypertension part 1 investigations on rats with genetically caused spontaneous hypertension. Medizinische Welt 23(25): 907-910

Yokoyama, S.; Asahara, H., 2011: The myogenic transcriptional network. Myogenesis has been a leading model for elucidating the molecular mechanisms that underlie tissue differentiation and development since the discovery of MyoD. During myogenesis, the fate of myogenic precursor cells is first determined by Pax3/Pax7...

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Schwartz, R.; Avello, E.; Palisson, F., 2008: Lamotrigine-induced toxic epidermal necrolysis treated with intravenous immunoglobulin and amniotic membranes. Archives of Dermatology 144(6): 724-726