Much research has focussed on the development of novel therapeutic agents to target various central nervous system disorders, however less attention has been given to determining the potential of ...such agents to permeate the blood‐brain barrier (BBB), a factor that will ultimately govern the effectiveness of these agents in man. In order to assess the potential for novel compounds to permeate the BBB, various in‐vitro, in‐vivo and in‐silico methods may be employed. Although in‐vitro models (such as primary cell culture and immortalized cell lines) are useful as a screening method and can appropriately rank compounds in order of BBB permeability, they often correlate poorly to in‐vivo brain uptake due to down‐regulation of some BBB‐specific transporters. In‐vivo models (such as the internal carotid artery single injection or perfusion, intravenous bolus injection, brain efflux index and intracerebral microdialysis) provide more accurate information regarding brain uptake, and these can be complemented with novel imaging techniques (such as magnetic resonance imaging and positron emission tomography), although such methods are not suited to high‐throughput permeability assessment. This paper reviews current methods used for assessing BBB permeability and highlights the particular advantages and disadvantages associated with each method, with a particular focus on methods suitable for moderate‐ to high‐throughput screening.
A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was ...employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation–reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs — MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation–reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.
Triglyceride mimetic prodrugs (2-MPA-TG) integrate into dietary triglyceride (TG) lymphatic transport pathways to promote drug delivery to lymphocytes in mesenteric lymph. Aliphatic ester (MPA-C8E,C18E) and amide (MPA-C18AM) prodrugs are less effective. Display omitted
The use of natural and synthetic lipids has generated much academic and commercial interest as a potential formulation strategy for improving the oral bioavailability of poorly water soluble drugs. ...Lipid-based formulations can reduce the inherent limitations of slow and incomplete dissolution of poorly water soluble drugs, and facilitate the formation of solubilised phases from which absorption may occur. The attainment of an appropriate pre-absorptive solubilised phase will not necessarily arise directly from the administered lipid, but most likely from the intraluminal processing to which lipids are subjected. This review attempts to provide a framework for the assessment of lipid based formulations by describing how aspects of GI physiology, and the choice of lipids and their formulation attributes, impact on dose form performance. Lipid digestion is briefly described and the various colloidal phases present within the GI tract during lipid digestion are highlighted. This is followed by selected examples where lipids have been investigated for improving the absorption of poorly water soluble drugs. Finally, some perspectives are offered such that the design of lipid-based dose forms may become less phenomenological than has been the traditional practice.
The trend towards identification of poorly water-soluble and highly lipophilic candidate drug molecules has led to an increase in interest in intestinal lymphatic drug transport. In this article we ...provide a brief background to the mechanism of access of drugs to the intestinal lymph and the role of lipid digestion and absorption in the stimulation of lymphatic transport. The ability of different lipid types to stimulate lymphatic drug transport, is addressed, concentrating specifically on the impact of the class, chain length and degree of unsaturation of co-administered lipids. Comment is also made as to the relevance of dosing different lipid volumes to the rat and the possible complications this may provide when trying to assess the likely extent of intestinal lymphatic transport. Recent studies are described in which the extent of lymphatic transport of a highly lipophilic antimalarial, halofantrine, was investigated after post-prandial administration to greyhound dogs. Finally the possible future directions for studies of intestinal lymphatic transport are discussed, including the use of cell culture models and genetically modified animals.
The histamine H
receptor is a G protein-coupled receptor (GPCR) drug target that is highly expressed in the CNS, where it acts as both an auto- and hetero-receptor to regulate neurotransmission. As ...such, it has been considered as a relevant target in disorders as varied as Alzheimer's disease, schizophrenia, neuropathic pain and attention deficit hyperactivity disorder. A range of competitive antagonists/inverse agonists have progressed into clinical development, with pitolisant approved for the treatment of narcolepsy. Given the breadth of compounds developed and potential therapeutic indications, we assessed the comparative pharmacology of six investigational histamine H
agents, including pitolisant, using native tissue and recombinant cells. Whilst all of the compounds tested displayed robust histamine H
receptor inverse agonism and did not differentiate between the main H
receptor splice variants, they displayed a wide range of affinities and kinetic properties, and included rapidly dissociating (pitolisant, S 38093-2, ABT-239) and slowly dissociating (GSK189254, JNJ-5207852, PF-3654746) agents. S 38093-2 had the lowest histamine H
receptor affinity (pK
values 5.7-6.2), seemingly at odds with previously reported, potent in vivo activity in models of cognition. We show here that at pro-cognitive and anti-hyperalgesic/anti-allodynic doses, S 38093-2 preferentially occupies the mouse sigma-1 receptor in vivo, only engaging the histamine H
receptor at doses associated with wakefulness promotion and neurotransmitter (histamine, ACh) release. Furthermore, pitolisant, ABT-239 and PF-3654746 also displayed appreciable sigma-1 receptor affinity, suggesting that this property differentiates clinically evaluated histamine H
receptor antagonists and may play a role in their efficacy.
Adenosine A
receptors (A
R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side ...effects such as bradycardia and altered renal hemodynamics. Biased agonism has emerged as an attractive mechanism for A
R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A
R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterized, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A
R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca
influx relative to NECA and the cAMP pathway at the A
R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A
R. In contrast to VCP746, which displays more 'adenosine-like' signaling at the A
R, neladenoson was a highly selective A
R agonist, with biased, weak agonism at the A
R. Together these results show that unwanted hemodynamic effects of A
R agonists can be avoided by compounds biased away from Ca
influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A
R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.
The intestinal mucosa is capable of metabolising drugs via phase I and II reactions. Increasingly, as a result of in vitro and in vivo (animal and human) data, the intestinal mucosa is being ...implicated as a major metabolic organ for some drugs. This has been supported by clinical studies of orally administered drugs (well-known examples include cyclosporin, midazolam, nifedipine and tacrolimus) where intestinal drug metabolism has significantly reduced oral bioavailability. This review discusses the intestinal properties and processes that contribute to drug metabolism. An understanding of the interplay between the processes controlling absorption, metabolism and P-glycoprotein-mediated efflux from the intestinal mucosa into the intestinal lumen facilitates determination of the extent of the intestinal contribution to first-pass metabolism. The clinical relevance of intestinal metabolism, however, depends on the relative importance of the metabolic pathway involved, the therapeutic index of the drug and the inherent inter- and intra-individual variability. This variability can stem from genetic (metabolising enzyme polymorphisms) and/or non-genetic (including concomitant drug and food intake, route of administration) sources. An overwhelming proportion of clinically relevant drug interactions where the intestine has been implicated as a major contributor to first-pass metabolism involve drugs that undergo cytochrome P450 (CYP) 3A4-mediated biotransformation and are substrates for the efflux transporter P-glycoprotein. Much work is yet to be done in characterising the clinical impact of other enzyme systems on drug therapy. In order to achieve this, the first-pass contributions of the intestine and liver must be successfully decoupled.
This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure−activity relationship in the context of physicochemical, biopharmaceutical, ...and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.
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