Altered brain exposure of morphine in experimental meningitis studied with microdialysis

Tunblad, Karin; Ederoth, Per; Gärdenfors, Anna; Hammarlund‐Udenaes, Margareta; Nordström, Carl‐Henrik

doi:10.1111/j.0001-5172.2003.0311.x

Cited by 37 publications

(20 citation statements)

References 22 publications

(20 reference statements)

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“…Morphine was studied in rats, in pigs with induced meningitis, and in humans with traumatic brain injury (1,100,105). Modeling of the blood-brain barrier transport was made on the rodent data but not of the pig or human data.…”

Section: Systems Pharmacology-related Examples Utilizing Microdialysismentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

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Abstract.Microdialysis has contributed with very important knowledge to the understanding of target-specific concentrations and their relationship to pharmacodynamic effects from a systems pharmacology perspective, aiding in the global understanding of drug effects. This review focuses on the historical development of microdialysis as a method to quantify the pharmacologically very important unbound tissue concentrations and of recent findings relating to modeling microdialysis data to extrapolate from rodents to humans, understanding distribution of drugs in different tissues and disease conditions. Quantitative microdialysis developed very rapidly during the early 1990s. Method development was in focus in the early years including development of quantitative microdialysis, to be able to estimate true extracellular concentrations. Microdialysis has significantly contributed to the understanding of active transport at the blood-brain barrier and in other organs. Examples are presented where microdialysis together with modeling has increased the knowledge on tissue distribution between species, in overweight patients and in tumors, and in metabolite contribution to drug effects. More integrated metabolomic studies are still sparse within the microdialysis field, although a great potential for tissue and disease-specific measurements is evident.

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Section: Systems Pharmacology-related Examples Utilizing Microdialysismentioning

confidence: 99%

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Hammarlund‐Udenaes

2017

AAPS J

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“…Before the publication of this expression in 2006, the efficiency of net active efflux or uptake for individual drugs had been described as the "ratio of unbound brain to unbound blood concentrations" Xie et al 2000;Bouw et al 2001;Tunblad et al 2003;Tunblad et al 2004a;Tunblad et al 2004b;Bostrom et al 2005;Tunblad et al 2005). BBB transport properties were thus separated from protein binding in plasma and binding to brain constituents, treating the three parameters as independent, individual properties of the drugs.…”

Section: Historical Aspects On Studying Brain Drug Deliverymentioning

confidence: 99%

Pharmacokinetic Concepts in Brain Drug Delivery

Hammarlund‐Udenaes

2013

Drug Delivery to the Brain

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This chapter presents the pharmacokinetic principles of blood-brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain . This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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“…Although there are many factors that can influence the pharmacokinetics / pharmacodynamics of a drug, transport of morphine across the blood-brain barrier (BBB) seems to be the most important step in permitting morphine to exert a centrally-mediated analgesic effect (5,6). The limitation of drug transport into the brain is determined by characteristics of the BBB, which in turn is affected by the physicochemical properties of drugs such as size, charge, and lipid solubility.…”

Section: Introductionmentioning

confidence: 99%

Negative Relationship Between Morphine Analgesia and P-Glycoprotein Expression Levels in the Brain

et al. 2007

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Abstract. It is known that opioid analgesics given systemically have limited distribution into the brain because of their interaction with P-glycoprotein (P-gp), an ATP-dependent efflux pump acting at the blood-brain barrier (BBB). We previously found that morphine and fentanyl showed higher analgesic potencies in P-gp-deficient mice compared with those in wild-type mice, suggesting that their analgesic effects are considerably dependent on P-gp expression. In this study, we focused on individual differences in the analgesic effectiveness of morphine, in cortical P-gp expression, and in basal P-gp ATPase activity in male ICR mice. We found that there were 3-to 10-fold differences between the magnitude of morphine analgesia (3 mg / kg, s.c.; tail-pinch method) in mice. Furthermore, there was a significant negative correlation between morphine's analgesic effects and individual P-gp expression in the cortex as estimated by western blot analysis. In addition, basal P-gp ATPase activities in isolated membrane preparations of brain capillary endothelial cells (BCECs) were negatively correlated with the magnitude of the analgesic effect of morphine. These results indicate that the individual differences in morphine analgesia may be due to some functional or quantitative differences in individual P-gp in BCECs, acting at the BBB.

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Altered brain exposure of morphine in experimental meningitis studied with microdialysis

Abstract: This study demonstrates that the morphine exposure to the brain is significantly increased during meningitis as compared with the control situation.

Cited by 37 publications

References 22 publications

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

Pharmacokinetic Concepts in Brain Drug Delivery

Negative Relationship Between Morphine Analgesia and P-Glycoprotein Expression Levels in the Brain

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