P-glycoprotein related drug interactions: clinical importance and a consideration of disease states.

Expert Opin Drug Metab Toxicol. 2010 May;6(5):603-19

Authors: Lee CA, Cook JA, Reyner EL, Smith DA

Abstract
IMPORTANCE OF THE FIELD: P-glycoprotein (P-gp) is the most characterized drug transporter in terms of its clinical relevance for pharmacokinetic disposition and interaction with other medicines. Clinically significant P-gp related drug interactions appear restricted to digoxin. P-gp may act as a major barrier to current and effective drug treatment in a number of diseases including cancer, AIDS, Alzheimer's and epilepsy due to its expression in tumors, lymphocytes, cell membranes of brain capillaries and the choroid plexus.
AREAS COVERED IN THIS REVIEW: This review summarizes the current understanding of P-gp structure/function, clinical importance of P-gp related drug interactions and the modulatory role this transporter may contribute towards drug efficacy in disease states such as cancer, AIDS, Alzheimer's and epilepsy.
WHAT THE READER WILL GAIN: The reader will gain an understanding that the clinical relevance of P-gp in drug interactions is limited. In certain disease states, P-gp in barrier tissues can modulate changes in regional distribution.
TAKE HOME MESSAGE: P-gp inhibition in isolation will not result in clinically important alterations in systemic exposure; however, P-gp transport may be of significance in barrier tissues (tumors, lymphocytes, brain) resulting in attenuated efficacy.

PMID: 20397967 [PubMed - indexed for MEDLINE]

Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents.

Cancer Chemother Pharmacol. 2010 Mar;65(4):625-39

Authors: O'Reilly T, McSheehy PM, Kawai R, Kretz O, McMahon L, Brueggen J, Bruelisauer A, Gschwind HP, Allegrini PR, Lane HA

Abstract
PURPOSE: Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice.
METHODS: Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity.
RESULTS: The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t(1/2), oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with similar C(max) and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose-dependent and showed over-proportional uptake in rats with a longer t(1/2) compared to the systemic circulation.
CONCLUSIONS: The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors.

PMID: 19784839 [PubMed - indexed for MEDLINE]

Saturation power dependence of amide proton transfer image contrasts in human brain tumors and strokes at 3 T.

Magn Reson Med. 2011 Oct;66(4):1033-41

Authors: Zhao X, Wen Z, Huang F, Lu S, Wang X, Hu S, Zu D, Zhou J

Abstract
Amide proton transfer (APT) imaging is capable of detecting mobile cellular proteins and peptides in tumor and monitoring pH effects in stroke, through the saturation transfer between irradiated amide protons and water protons. In this work, four healthy subjects, eight brain tumor patients (four with high-grade glioma, one with lung cancer metastasis, and three with meningioma), and four stroke patients (average 4.3 ± 2.5 days after the onset of the stroke) were scanned at 3 T, using different radiofrequency saturation powers. The APT effect was quantified using the magnetization transfer ratio (MTR) asymmetry at 3.5 ppm with respect to the water resonance. At a saturation power of 2 ?T, the measured APT-MRI signal of the normal brain tissue was almost zero, due to the contamination of the negative conventional magnetization transfer ratio asymmetry. This irradiation power caused an optimal hyperintense APT-MRI signal in the tumor and an optimal hypointense signal in the stroke, compared to the normal brain tissue. The results suggest that the saturation power of 2 ?T is ideal for APT imaging of these two pathologies at 3 T with the existing clinical hardware.

PMID: 21394783 [PubMed - indexed for MEDLINE]

SMOC1 is a tenascin-C interacting protein over-expressed in brain tumors.

Matrix Biol. 2011 Apr;30(3):225-33

Authors: Brellier F, Ruggiero S, Zwolanek D, Martina E, Hess D, Brown-Luedi M, Hartmann U, Koch M, Merlo A, Lino M, Chiquet-Ehrismann R

Abstract
Tenascin-C is an extracellular matrix protein over-expressed in a large variety of cancers. In the present study, we aimed at identifying new interactors of tenascin-C by purifying secreted proteins on a tenascin-C affinity column. Analysis of eluates by mass spectrometry revealed phosphoglycerate kinase 1, clusterin, fibronectin, SPARC-related modular calcium-binding protein 1 (SMOC1) and nidogen-2 as potential interactors of tenascin-C. The interaction between tenascin-C and SMOC1 was confirmed by co-immunoprecipitation and further analyzed by Surface Plasmon Resonance Spectroscopy, which revealed an apparent dissociation constant (K(D)) value of 2.59?10(-9)M. Further analyses showed that this binding is reduced in the presence of EDTA. To investigate whether SMOC1 itself could be over-expressed in the context of tumorigenesis, we analyzed data of two independent RNA profiling studies and found that mRNA levels of SMOC1 are significantly increased in oligodendrogliomas compared to control brain samples. In support of these data, western blot analysis of protein extracts from 12 oligodendrogliomas, 4 astrocytomas and 13 glioblastomas revealed elevated levels compared to healthy brain extract. Interestingly, cell migration experiments revealed that SMOC1 can counteract the chemo-attractive effect of tenascin-C on U87 glioma cells. The present study thus identified SMOC1 as a new cancer-associated protein capable of interacting with tenascin-C in vitro.

PMID: 21349332 [PubMed - indexed for MEDLINE]