Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid concentrations in rhesus monkeys.
ABSTRACT Brain penetration of drugs which are subject to P-glycoprotein (Pgp)-mediated efflux is attenuated, as manifested by the fact that the cerebrospinal fluid concentration (C(CSF)), a good surrogate of the unbound brain concentration (C(ub)), is lower than the unbound plasma concentration (C(up)) for Pgp substrates. In rodents, the attenuation magnitude of brain penetration by Pgp-mediated efflux has been estimated by correlating the ratio of CSF to plasma exposures (C(CSF)/C(p)) with the unbound fraction in plasma (f(u)) upon the incorporation of the in vivo or in vitro Pgp-mediated efflux ratios (ERs). In the present work, we investigated the impact of Pgp-mediated efflux on C(CSF) in monkeys. Following intravenous administration to cisterna magna ported rhesus monkeys, the CSF and plasma concentrations were determined for 25 compounds from three discovery programs. We also evaluated their f(u) in rhesus plasma and ER in human and African green monkey MDR-transfected LLC-PK1 cells. These compounds varied significantly in the f(u) (0.025-0.73), and 24 out of 25 are considered Pgp substrates based on their appreciable directional transport (ER>2). The C(CSF)/C(p) was significantly lower than the corresponding f(u) (>or=3-fold) for 16 compounds regardless of a significant correlation (R(2)=0.59, p=4 x 10(-5)) when the C(CSF)/C(p) was plotted against the f(u). When the f(u) was normalized to the ER (f(u)/ER) the correlation was improved (R(2)=0.75, p=8 x 10(-8)). More importantly, only one compound showed the C(CSF)/C(p) that exceeded 3-fold of the normalized f(u). The results suggest that the impact of Pgp-mediated efflux in monkeys, similar to the case in rodents, is reasonably reflected by the gradient between the free concentrations in plasma and in CSF. Therefore, f(u) and Pgp ER may serve as useful measurements in estimating in vivo C(CSF)/C(p) ratios in monkeys, and potentially in humans.
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ABSTRACT: In this chapter, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing and understanding the underlying mechanisms of DDIs. In vivo assessments in an appropriate animal model are considered key to help verify in vivo relevance of in vitro studies and substantiate a basis for extrapolating in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, an important consideration for successful selection of the animal model is based on broad similarities to humans in key physiological and biochemical parameters governing drug absorption, distribution, metabolism, or excretion (ADME) process of interest for both the interacted and the interacting drugs. Also equally important are specific in vitro and/or in vivo experiments demonstrating animal–human similarities, usually both qualitative and quantitative, in the ADME property/process under investigation. Additional insights can also be gained with the use of knockout animals lacking specific drug transporters or drug-metabolizing enzymes and/or transgenic animal models with humanized mouse lines expressing specific drug transporters and/or metabolizing enzymes of interest.12/2009: pages 283-297;
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ABSTRACT: Introduction: It is becoming increasingly evident that transporters play an important role in the absorption, distribution and elimination of many drugs. Different approaches have been developed and validated to understand the interactions between drugs and transporters, and the in vivo role of drug transporters. These tools are helping to understand the impact of transporters on the pharmacokinetics (PK) of drugs and assess the risk of drug-drug interactions (DDIs) in drug discovery and development. Areas covered: This article provides an overview of different approaches to evaluate the drug transporters involved in intestinal absorption, hepatic and renal clearance, and brain penetration. Specifically, it provides the best practices to evaluate the major uptake and efflux transporters in drug discovery. It also discusses the challenges and gaps in understanding the clinical relevance of drug transporters. Expert opinion: Quantitative prediction of transporter-mediated clearance, tissue exposure, as well as DDIs is still limited. The current challenge is to develop in vitro-in vivo correlations, extrapolate and integrate data from in vitro transporter assays, and preclinical species into humans to quantitatively predict the impact of transporters on drug absorption, disposition, elimination and DDIs. With the development of a variety of novel tools, the ultimate goal is to use high quality in vitro and in vivo data to establish physiologically based PK models, which will improve the capability to predict PK, tissue exposure and DDIs in humans.Expert Opinion on Drug Discovery 05/2014; · 3.47 Impact Factor
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ABSTRACT: The unbound drug concentration in brain parenchyma is considered to be the relevant driver for interaction with CNS biological targets. Drug levels in cerebrospinal fluid (C_CSF) are frequently used surrogates for the unbound concentrations in brain. For drugs actively transported across the blood-brain barrier (BBB), C_CSF differs from unbound plasma concentration (Cu_p) to an extent that is commonly unknown. In this study, the relationship between CSF-to-unbound plasma drug partitioning in rats and the mouse Pgp (Mdr1a) efflux ratio (ER) obtained from in vitro transcellular studies has been investigated for a set of 61 CNS compounds exhibiting substantial diversity in chemical structure and physico-chemical properties. In order to understand the in vitro-in vivo extrapolation of Pgp efflux, a mechanistic model was derived relating in vivo CNS distribution kinetics to in vitro active transport. The model was applied to predict C_CSF from Cu_p and ER data for 19 proprietary Roche CNS drug candidates. The calculated CSF concentrations were correlated with CNS pharmacodynamic responses observed in rodent models. The correlation between in vitro and in vivo potency for different pharmacological endpoints indicated that the predicted C_CSF is a valuable surrogate of the concentration at the target site. Overall, C_CSF proved superior description of PK/PD data than unbound plasma or total brain concentration for Mdr1a substrates. Predicted C_CSF can be used as a default approach to understand the PK/PD relationships in CNS efficacy models and can support the extrapolation of efficacious brain exposure for new drug candidates from rodent to man.Biochemical pharmacology 02/2013; · 4.25 Impact Factor