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A G Ellis, M M Doherty,
F Walker,
J Weinstock,
M Nerrie,
A Vitali,
R Murphy,
T G Johns,
A M Scott,
A Levitzki,
G McLachlan,
L K Webster,
A W Burgess,
E C Nice
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ABSTRACT: The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30-48 min). The linear relationship between dose and AUC(0-->infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.
Biochemical Pharmacology 05/2006; 71(10):1422-34. · 4.70 Impact Factor
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ABSTRACT: Drug-metabolizing enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics, including antineoplastics, resulting in either their activation or detoxification. Many studies have reported the presence of DME in tumors; however, heterogeneous detection methodology and patient cohorts have not generated consistent, firm data. Nevertheless, various gene therapy approaches and oral prodrugs have been devised, taking advantage of tumoral DME. With the need to target and individualize anticancer therapies, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses cytotoxic drug metabolism by tumors, through addressing the classes of the individual DME, their relevant substrates, and their distribution in specific malignancies. The limitations of preclinical models relative to the clinical setting and lack of data on the changes of DME with disease progression and host response will be discussed. The therapeutic implications of tumoral drug metabolism will be addressed-in particular, the role of DME in predicting therapeutic response, the activation of prodrugs, and the potential for modulation of their activity for gain are considered, with relevant clinical examples. The contribution of tumoral drug metabolism to cancer therapy can only be truly ascertained through large-scale prospective studies and supported by new technologies for tumor sampling and genetic analysis such as microarrays. Only then can efforts be concentrated in the design of better prodrugs or combination therapy to improve drug efficacy and individualize therapy.
Journal of Clinical Oncology 02/2005; 23(1):205-29. · 18.37 Impact Factor
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ABSTRACT: Drug metabolising enzymes (DME) in tumors are capable of biotransforming a variety of xenobiotics. Over a long period of time, many studies have reported the presence of DME in tumors, however quantitation and sampling techniques and heterogeneous patient populations have resulted in many generalisations, provoking more questions than they answer. In addition, many of the studies have focussed on a potential role of DME in procarcinogenesis rather than for modulation for therapeutic advantage. With the need to target anticancer therapies to tumor cells to avoid undesirable systemic effects, tumoral processes such as drug metabolism must be considered as both a potential mechanism of resistance to therapy and a potential means of achieving optimal therapy. This review discusses drug metabolism by tumors by firstly addressing the level and activity of individual DME in the common cancers: breast, gastrointestinal, brain, lung and haematological malignancies in comparison to peritumoral and nontumoral tissue. This is then put into perspective through consideration of the therapeutic implications of tumoral drug metabolism especially with regard to the new anticancer agents. The contribution of tumoral metabolism and its significance in cancer therapy must be ascertained through prospective studies. Only then can efforts be concentrated in the design of better prodrugs or combinations of therapy to improve intracellular drug concentrations. Various gene therapy approaches have been attempted experimentally with promising results. However, there are major gaps in understanding the implications of tumoral DME in disease progression (including metastasized tissue) and relapse.
Current Drug Metabolism 05/2003; 4(2):131-49. · 5.11 Impact Factor
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ABSTRACT: Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.
Anesthesia & Analgesia 12/1996; 83(6):1244-50. · 3.29 Impact Factor
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ABSTRACT: We evaluated the utility of medium molecular weight hyaluronic acid for prolonging the local anesthetic activity of lidocaine in a rabbit model of epidural analgesia. Equiviscous formulations were prepared as either a physical mixture of lidocaine hydrochloride and sodium hyaluronate (where drug release occurred via diffusion) or as a lidocaine-hyaluronate complex (where drug release occurred via diffusional and electrostatic processes). The novel hyaluronic acid formulations were functionally evaluated, relative to lidocaine solution, in an intact, conscious rabbit model. The hyaluronate formulations were well tolerated. The duration of sensory block and loss of weight-bearing was prolonged twofold by the lidocaine-hyaluronate complex relative to the solution (P < 0.05). In terms of motor block, flaccid paresis occurred after administration of the solution formulation, whereas only partial motor block was evident after administration of the viscous formulations. Pharmacokinetic modeling of the lidocaine plasma concentration-time data indicated that the rate of drug absorption from the lidocaine-hyaluronate complex was decreased fourfold relative to the solution (P < 0.05). These observations indicate that ionic complexes of local anesthetics with medium molecular weight hyaluronic acid may offer advantages for the prolongation of epidural analgesia.
Anesthesia & Analgesia 04/1995; 80(4):740-6. · 3.29 Impact Factor
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ABSTRACT: A rabbit model is described for the evaluation of epidurally administered local anaesthetic agents. The technique involves a single injection via the readily identified lumbosacral space in conscious rabbits, with the epidural space being identified by a modified loss-of-resistance technique. The endpoints used to assess pharmacodynamic responses of the rabbit model were (1) sensory loss, (2) loss of weight-bearing ability, and (3) flaccid paresis. The model was further characterised by investigation of endpoint responses to changes in injection volume (0.1-0.25 ml/kg) and concentration of administered lignocaine solutions (0.5 to 2%). From these studies, a volume of 0.2 ml/kg was chosen as a standard dose and a subsequent comparison between different agents undertaken. The rank order for the onset of action, duration of effect and the observed pharmacokinetic profiles after epidural administration of 2% lignocaine, 2% lignocaine with adrenaline (1:200,000) or 0.5% bupivacaine solutions are broadly consistent with human clinical data. These data indicate that the rabbit is a simple (albeit limited) model for the screening evaluation of epidurally administered local anaesthetic agents.
Anaesthesia and intensive care 07/1993; 21(3):298-303. · 1.28 Impact Factor
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A.G. Ellis, M.M. Doherty,
F. Walker,
J. Weinstock,
M. Nerrie,
A. Vitali,
R. Murphy,
T.G. Johns,
A.M. Scott,
A. Levitzki,
G. McLachlan,
L.K. Webster,
A.W. Burgess,
E.C. Nice
[show abstract]
[hide abstract]
ABSTRACT: The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short (<24 min) effective inhibition of cellular receptor response to EGF challenge in BaF/ERX cells indicating a need to maintain sustained levels of inhibitor. Initial pharmacokinetic evaluation in mice of novel AG1478 formulations in a beta-cyclodextrin (Captisol®) showed monoexponential elimination from plasma (half-life 30 min) following subcutaneous administration. A two-fold dose escalation gave a 2.4-fold increase in the total AUC. Bolus i.v. and 6 h continuous infusion were investigated in rats to mimic a more clinically relevant administration regimen. Drug elimination following bolus i.v. administration was biphasic (terminal elimination half-life 30–48 min). The linear relationship between dose and AUC0→∞ (r2 = 0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478 >10 μM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.Δ2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.
Biochemical Pharmacology.
