In Vitro P-glycoprotein Efflux Ratio Can Predict the In Vivo Brain Penetration Regardless of Biopharmaceutics Drug Disposition Classification System Class

Kikuchi, Ryota; Morais, Sonia M. de; Kalvass, J. Cory

doi:10.1124/dmd.113.053868

Cited by 61 publications

(49 citation statements)

References 25 publications

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“…The BBB, which is formed by endothelial cells, limits the rapid and free exchange of drugs between the CNS and blood because of the highly developed tight junctions between adjacent endothelial cells (de Lange and Danhof, 2002;Abbott, 2004) and also of the active efflux mediated by P-glycoprotein (P-gp/MDR1/ABCB1), breast cancer resistance protein (Bcrp/ABCG2), and multidrug resistance-associated protein 4 (MRP4/ABCC4) (Schinkel, 1999;Leggas et al, 2004;Belinsky et al, 2007;Enokizono et al, 2007Enokizono et al, , 2008Ose et al, 2009). In fact, the C brain of drugs, and consequently the C u,brain , is inversely correlated with the activity of P-gp (Kikuchi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Investigation of the Brain-to-Cerebrospinal Fluid Unbound Drug Concentration Ratio under Steady-State Conditions in Rats Using a Pharmacokinetic Model and Scaling Factors for Active Efflux Transporters

Kodaira

Kusuhara

Fuse³

et al. 2014

Drug Metab Dispos

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A pharmacokinetic model was constructed to explain the difference in brain-and cerebrospinal fluid (CSF)-to-plasma and brainto-CSF unbound drug concentration ratios (K p,uu,brain , K p,uu,CSF , and K p,uu,CSF/brain , respectively) of drugs under steady-state conditions in rats. The passive permeability across the blood-brain barrier (BBB), PS 1 , was predicted by two methods using log(D/molecular weight 0.5 ) for PS 1 (1) or the partition coefficient in octanol/water at pH 7.4 (LogD), topologic van der Waals polar surface area, and van der Waals surface area of the basic atoms for PS 1 (2). The coefficients of each parameter were determined using previously reported in situ rat BBB permeability. Active transport of drugs by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) measured in P-gp-and Bcrp-overexpressing cells was extrapolated to in vivo by introducing scaling factors. Brain-and CSF-toplasma unbound concentration ratios (K p,uu,brain and K p,uu,CSF , respectively) of 19 compounds, including P-gp and Bcrp substrates (daidzein, dantrolene, flavopiridol, genistein, loperamide, quinidine, and verapamil), were simultaneously fitted to the equations in a three-compartment model comprising blood, brain, and CSF compartments. The calculated K p,uu,brain and K p,uu,CSF of 17 compounds were within a factor of three of experimental values. K p,uu,CSF values of genistein and loperamide were outliers of the prediction, and K p,uu,brain of dantrolene also became an outlier when PS 1 (2) was used. K p,uu,CSF/brain of the 19 compounds was within a factor of three of experimental values. In conclusion, the K p,uu,CSF/brain of drugs, including P-gp and Bcrp substrates, could be successfully explained by a kinetic model using scaling factors combined with in vitro evaluation of P-gp and Bcrp activities.

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Section: Introductionmentioning

confidence: 99%

Quantitative Investigation of the Brain-to-Cerebrospinal Fluid Unbound Drug Concentration Ratio under Steady-State Conditions in Rats Using a Pharmacokinetic Model and Scaling Factors for Active Efflux Transporters

Kodaira

Kusuhara

Fuse³

et al. 2014

Drug Metab Dispos

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“…However, it is obvious that even in wild type mice, where P-gp may be highly expressed in brain, the Kp,uu,brain values of all antidepressants in the list are still higher than 0.1 and 0.33, ranging from 0.56 to 1.67. As drugs with Kp,uu,brain values greater than or equal to 0.33 [38, 40] and 0.1 [54] are assigned as BBB+, this indicates that all of the antidepressants listed in Table 4 can penetrate into mouse brain.…”

Section: Reliability Of Methods To Evaluate Brain Penetration Of Amentioning

confidence: 99%

“…However, there are relatively few publications that define the appropriate cut-off for expected CNS activity following clinically relevant doses. In 2007 Kalvass et al [38] proposed a cut-off of 0.33, with K p,uu, brain values less than 0.33 indicating poor brain exposure, and reiterated this choice more recently [40]. …”

Section: Blood-brain Barrier (Bbb)mentioning

confidence: 99%

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Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain

2015

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As P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an increasing number of publications addressed the effect of P-gp in limiting brain penetration of antidepressants and causing treatment-resistant depression in current clinical therapies. However, contradictory results were observed in different systems. It is of vital importance to understand the potential for drug interactions related to P-gp at the blood-brain barrier (BBB), and whether co-administration of a P-gp inhibitor together with an antidepressant is a good clinical strategy for dosing of patients with treatment-resistant depression. In this review, the complicated construction of the BBB, the transport mechanisms for compounds that cross the BBB, and the basic characteristics of antidepressants are illustrated. Further, the reliability of different systems related to antidepressant brain delivery, including in vitro bidirectional transport cell lines, in vivo Mdr1 knock-out mice, and chemical inhibition studies in rodents are analyzed, supporting a low possibility that P-gp affects currently marketed antidepressants when these results are extrapolated to human BBB. These findings can also be applied to other central nervous system drugs.

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“…Here Kikuchi et al (2013) review the evidence for the utility of the BDDCS in predicting brain penetration from in vitro-derived P-gp efflux ratios.…”

mentioning

confidence: 99%

Prediction of Human Pharmacokinetics in 2013 and Beyond

Houston

2013

Drug Metab Dispos

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The utility of in vitro generated kinetic data to provide quantitative prediction of in vivo pharmacokinetic behavior is well established and forms a cornerstone of many research projects in drug metabolism and disposition, particularly within the pharmaceutical industry. This issue provides several excellent examples of the use of in vitro techniques for prediction of human pharmacokinetics (PK). The general area of in vitro-in vivo extrapolation (IVIVE) is broad and hence the spectrum of topics covers various aspects drug clearance and distribution and drug-drug interactions. Some articles were commissioned whereas others were identified during the reviewing process. Overall they provide a snapshot of activity at the end of 2013. They document that whereas the translation of some in vitro approaches is now established, other areas are in their infancy and need more development.Prediction of metabolic clearance is an example of a mature in vitro-in vivo extrapolation (IVIVE) area. Di et al. (2013a) provide here an overview of best practices and illustrate a wide application. The area is dominated by examples of hepatic cytochrome P450 (P450), but application beyond P450 enzymes to UDP-glucuronosyltransferases (UGTs) and aldehyde oxidase are now evident. Clearance prediction, and IVIVE in general, is increasingly coupled with physiologically based pharmacokinetic (PBPK) models to allow prediction not limited to specific parameters but to generate a time course that can further inform quantitative aspects of drug absorption, distribution, metabolism, and excretion processes (as outlined here by Shardlow et al., 2013). The dynamic rather than static approaches with a time dimension rather than a time-averaged estimate results in far more comprehensive usage of the in vitro data. An excellent example is contained in this issue (Xu et al., 2013), where the importance of CYP2B6 polymorphisms is explored in defining efavirenz clearance.Prediction of transporter hepatic clearance is an area of great interest and contrasts markedly with the state of play for metabolic hepatic clearance. The complexity of this is becoming evident when delineating the interrelationships between not only enzymes and transporters but also between uptake and efflux transporters and between transporters and passive processes acknowledged (Parker and Houston, 2008;Yabe et al., 2011;Jones et al., 2012; Menochet et al., 2012). It would appear that multiple in vitro models are required, and to integrate these different sources of data requires PBPK modeling procedures. This and other aspects of best practices for transporter-related parameter estimations and predictions have been collated by the International Transporter Consortium (Zamek-Gliszczynski et al., 2013).The balance of active and passive processes in membrane transport of drugs is often helped by consideration of the Biopharmaceutical Drug Disposition Classification System (BDDCS) (Wu and Benet, 2005). Here Kikuchi et al. (2013) review the evidence for the utility of the BDDCS ...

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In Vitro P-glycoprotein Efflux Ratio Can Predict the In Vivo Brain Penetration Regardless of Biopharmaceutics Drug Disposition Classification System Class

Cited by 61 publications

References 25 publications

Quantitative Investigation of the Brain-to-Cerebrospinal Fluid Unbound Drug Concentration Ratio under Steady-State Conditions in Rats Using a Pharmacokinetic Model and Scaling Factors for Active Efflux Transporters

Quantitative Investigation of the Brain-to-Cerebrospinal Fluid Unbound Drug Concentration Ratio under Steady-State Conditions in Rats Using a Pharmacokinetic Model and Scaling Factors for Active Efflux Transporters

Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain

Prediction of Human Pharmacokinetics in 2013 and Beyond

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