Strategies for Increasing Drug Delivery to the Brain
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Clin Pharmacokinet 2002; 41 (3): 171-186 0312-5963/02/0003-0171/$25.00/0 © Adis International Limited. All rights reserved.
Strategies for Increasing Drug Delivery to the Brain Focus on Brain Lymphoma Tali Siegal1 and Ester Zylber-Katz2 1 Neuro-Oncology Center, Hadassah Hebrew University Hospital, Jerusalem, Israel 2 Clinical Pharmacology Unit, Division of Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
Abstract
The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. The current concept is that inadequate drug delivery is a major factor that explains the unsatisfactory response of chemosensitive brain tumours. Various strategies have been devised to circumvent the BBB in order to increase drug delivery to the CNS. The various approaches can be categorised as those that attempt to increase delivery of intravascularly administered drugs, and those that attempt to increase delivery by local drug administration. Strategies that increase delivery of intravascularly injected drugs can manipulate either the drugs or the capillary permeability of the various barriers (BBB or blood-tumour barrier), or may attempt to increase plasma concentration or the fraction of the drug reaching the tumour (high-dose chemotherapy, intra-arterial injection). Neurotoxicity is a major concern with increased penetration of drugs into the CNS or when local delivery is practised. Systemic toxicity remains the limiting factor for most methods that use intravascular delivery. This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.
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Numerous chemotherapeutic agents with favourable activity in in vitro studies prove ineffective in animal models or in patients. This in vivo ineffectiveness is often explained as insufficient penetration of the drug to the desired site of action in concentrations adequate to exert a pharmacological effect.[1] The blood-brain barrier (BBB) is one such typical impediment. The BBB is both a physical and a functional gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial issue. On the whole, inadequate drug delivery and development of tumour cell resistance are the major factors used to ex
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