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The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid.

Westerhout J, Smeets J, Danhof M, de Lange EC - J Pharmacokinet Pharmacodyn (2013)

Bottom Line: It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations.This relationship is significantly influenced by activity of P-gp.Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

ABSTRACT
In the development of central nervous system (CNS)-targeted drugs, the prediction of human CNS target exposure is a big challenge. Cerebrospinal fluid (CSF) concentrations have often been suggested as a 'good enough' surrogate for brain extracellular fluid (brainECF, brain target site) concentrations in humans. However, brain anatomy and physiology indicates prudence. We have applied a multiple microdialysis probe approach in rats, for continuous measurement and direct comparison of quinidine kinetics in brainECF, CSF, and plasma. The data obtained indicated important differences between brainECF and CSF kinetics, with brainECF kinetics being most sensitive to P-gp inhibition. To describe the data we developed a systems-based pharmacokinetic model. Our findings indicated that: (1) brainECF- and CSF-to-unbound plasma AUC0-360 ratios were all over 100 %; (2) P-gp also restricts brain intracellular exposure; (3) a direct transport route of quinidine from plasma to brain cells exists; (4) P-gp-mediated efflux of quinidine at the blood-brain barrier seems to result of combined efflux enhancement and influx hindrance; (5) P-gp at the blood-CSF barrier either functions as an efflux transporter or is not functioning at all. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations. This relationship is significantly influenced by activity of P-gp. Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.

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Average (geometric mean ± SEM) unbound quinidine concentration–time profiles following intravenous administration of quinidine, with (+) or without (−) co-administration of tariquidar (15/mg/kg). a 10 mg/kg quinidine dose: for plasma (n = 11 (−) and 6 (+)), brainECF (n = 6 (−) and 4 (+)), CSFLV (n = 4 (−) and 3 (+)) and CSFCM (n = 4 (−) and 4 (+). b 20 mg/kg quinidine dose. Plasma (n = 9 (−) and 11 (+)), brainECF (n = 5 (−) and 6 (+)), CSFLV (n = 4 (−) and 4 (+)) and CSFCM (n = 6 (−) and 6 (+))
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Fig1: Average (geometric mean ± SEM) unbound quinidine concentration–time profiles following intravenous administration of quinidine, with (+) or without (−) co-administration of tariquidar (15/mg/kg). a 10 mg/kg quinidine dose: for plasma (n = 11 (−) and 6 (+)), brainECF (n = 6 (−) and 4 (+)), CSFLV (n = 4 (−) and 3 (+)) and CSFCM (n = 4 (−) and 4 (+). b 20 mg/kg quinidine dose. Plasma (n = 9 (−) and 11 (+)), brainECF (n = 5 (−) and 6 (+)), CSFLV (n = 4 (−) and 4 (+)) and CSFCM (n = 6 (−) and 6 (+))

Mentions: The average unbound plasma (plasmau) and unbound brain (brainu) quinidine concentrations following the 10 and 20 mg/kg dose with or without co-administration of tariquidar are shown in Fig. 1. Plasma protein binding of quinidine was linear at an extent of 86.5 ± 5.5 %. It was not affected by co-administration of tariquidar. The co-administration of tariquidar slightly reduced the plasma elimination rate of plasmau for both 10 and 20 mg/kg dose of quinidine. Data obtained by microdialysis from the brainECF, LV (CSFLV) and CM (CSFCM) were corrected for in vivo recovery. The average in vivo recoveries for the brainu concentrations in ST, LV and CM probes were not influenced by co-administration of tariquidar and were determined to be 9.1 ± 0.5, 2.9 ± 0.5 and 3.5 ± 0.5 %, respectively.Fig. 1


The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid.

Westerhout J, Smeets J, Danhof M, de Lange EC - J Pharmacokinet Pharmacodyn (2013)

Average (geometric mean ± SEM) unbound quinidine concentration–time profiles following intravenous administration of quinidine, with (+) or without (−) co-administration of tariquidar (15/mg/kg). a 10 mg/kg quinidine dose: for plasma (n = 11 (−) and 6 (+)), brainECF (n = 6 (−) and 4 (+)), CSFLV (n = 4 (−) and 3 (+)) and CSFCM (n = 4 (−) and 4 (+). b 20 mg/kg quinidine dose. Plasma (n = 9 (−) and 11 (+)), brainECF (n = 5 (−) and 6 (+)), CSFLV (n = 4 (−) and 4 (+)) and CSFCM (n = 6 (−) and 6 (+))
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4269305&req=5

Fig1: Average (geometric mean ± SEM) unbound quinidine concentration–time profiles following intravenous administration of quinidine, with (+) or without (−) co-administration of tariquidar (15/mg/kg). a 10 mg/kg quinidine dose: for plasma (n = 11 (−) and 6 (+)), brainECF (n = 6 (−) and 4 (+)), CSFLV (n = 4 (−) and 3 (+)) and CSFCM (n = 4 (−) and 4 (+). b 20 mg/kg quinidine dose. Plasma (n = 9 (−) and 11 (+)), brainECF (n = 5 (−) and 6 (+)), CSFLV (n = 4 (−) and 4 (+)) and CSFCM (n = 6 (−) and 6 (+))
Mentions: The average unbound plasma (plasmau) and unbound brain (brainu) quinidine concentrations following the 10 and 20 mg/kg dose with or without co-administration of tariquidar are shown in Fig. 1. Plasma protein binding of quinidine was linear at an extent of 86.5 ± 5.5 %. It was not affected by co-administration of tariquidar. The co-administration of tariquidar slightly reduced the plasma elimination rate of plasmau for both 10 and 20 mg/kg dose of quinidine. Data obtained by microdialysis from the brainECF, LV (CSFLV) and CM (CSFCM) were corrected for in vivo recovery. The average in vivo recoveries for the brainu concentrations in ST, LV and CM probes were not influenced by co-administration of tariquidar and were determined to be 9.1 ± 0.5, 2.9 ± 0.5 and 3.5 ± 0.5 %, respectively.Fig. 1

Bottom Line: It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations.This relationship is significantly influenced by activity of P-gp.Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

ABSTRACT
In the development of central nervous system (CNS)-targeted drugs, the prediction of human CNS target exposure is a big challenge. Cerebrospinal fluid (CSF) concentrations have often been suggested as a 'good enough' surrogate for brain extracellular fluid (brainECF, brain target site) concentrations in humans. However, brain anatomy and physiology indicates prudence. We have applied a multiple microdialysis probe approach in rats, for continuous measurement and direct comparison of quinidine kinetics in brainECF, CSF, and plasma. The data obtained indicated important differences between brainECF and CSF kinetics, with brainECF kinetics being most sensitive to P-gp inhibition. To describe the data we developed a systems-based pharmacokinetic model. Our findings indicated that: (1) brainECF- and CSF-to-unbound plasma AUC0-360 ratios were all over 100 %; (2) P-gp also restricts brain intracellular exposure; (3) a direct transport route of quinidine from plasma to brain cells exists; (4) P-gp-mediated efflux of quinidine at the blood-brain barrier seems to result of combined efflux enhancement and influx hindrance; (5) P-gp at the blood-CSF barrier either functions as an efflux transporter or is not functioning at all. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations. This relationship is significantly influenced by activity of P-gp. Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.

Show MeSH
Related in: MedlinePlus