M M Doherty

Victorian College for the Deaf, Melbourne, Victoria, Australia

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Publications (11)54.31 Total impact

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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. DOI:10.1016/j.bcp.2006.01.020 · 4.65 Impact Factor
  • M Michael, M M Doherty
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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. DOI:10.1200/JCO.2005.02.120 · 17.88 Impact Factor
  • M M Doherty, M Michael
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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. DOI:10.2174/1389200033489497 · 3.49 Impact Factor
  • Margaret M Doherty, William N Charman
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    ABSTRACT: 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.
    Clinical Pharmacokinetics 02/2002; 41(4):235-53. · 5.49 Impact Factor
  • M M Doherty, K S Pang
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    ABSTRACT: 1. To compare the disposition of tracer morphine ([3H]M) following systemic and intraduodenal administration in the recirculating, rat small intestine preparation in absence or presence of verapamil (V), an inhibitor of P-glycoprotein. 2. To develop a physiological model to explain the observations. A bolus dose of [3H]M was added to the reservoir or injected into the duodenum of the rat small intestine preparation. V (200 microM in reservoir) was either absent (control studies) or present. Intestinal microsomal, incubation studies were performed to evaluate the effect of V on morphine glucuronidation. After systemic administration, [3H]M was not metabolized but was exsorbed into lumen. By contrast, both [3H]M and the 3beta-glucuronide metabolite, [3H]M3G, appeared in reservoir and lumen after intraduodenal administration. A physiologically-based model that encompassed absorption, metabolism and secretion was able to describe the route-dependent glucuronidation of M. The presence of V resulted in diminished levels of M3G in perfusate and lumen and mirrored the observation of decreased glucuronidation in microsomal incubations. Verapamil appeared to be an inhibitor of glucuronidation and not secretion of M. M was secreted and absorbed by the rat small intestine. Route-dependent glucuronidation of M was explained by physiological modeling when M was poorly partitioned in intestinal tissue, with a low influx clearance from blood and a even poorer efflux clearance from tissue. The poor efflux rendered a much greater metabolism of M that was initially absorbed from the lumen. V increased the extent of M absorption through inhibition of M glucuronidation.
    Pharmaceutical Research 04/2000; 17(3):291-8. DOI:10.1023/A:1007548905772 · 3.95 Impact Factor
  • D Cong, M Doherty, K S Pang
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    ABSTRACT: Processes of intestinal absorption, metabolism, and secretion must be considered simultaneously in viewing oral drug bioavailability. Existing models often fail to predict route-dependent intestinal metabolism, namely, little metabolism occurs after systemic dosing but notable metabolism exists after oral dosing. A physiologically based, Segregated-Flow Model (SFM) was developed to examine the influence of intestinal transport (absorption and exsorption), metabolism, flow, tissue-partitioning characteristics, and elimination in other organs on intestinal clearance, intestinal availability, and systemic bioavailability. For the SFM, blood flow to intestine was effectively segregated for the perfusion of two regions, with 10% reaching an absorptive layer-the enterocytes at the villus tips of the mucosa where metabolic enzymes and the P-glycoprotein reside, and the remaining 90% supplying the rest of the intestine (serosa and submucosa), a nonabsorptive layer. The traditional, physiologically-based model, which regards the intestine as a single, homogeneous compartment with all of the intestinal blood flow perfusing the tissue, was also examined for comparison. The analytical solutions under first order conditions were essentially identical for the SFM and traditional model, differing only in the flow rate to the absorptive/removal region. The presence of other elimination organs did not affect the intestinal clearance and bioavailability estimates, but reduced the percentage of dose metabolized by the intestine. For both models, intestinal availability was inversely related to the intrinsic clearances for intestinal metabolism and exsorption, and was additionally affected by both the rate constant for absorption and that denoting luminal loss when drug was exsorbed. However, the effect of secretion by P-glycoprotein became attenuated with rapid absorption. The difference in flow between models imparted a substantial influence on the intestinal clearance of flow-limited substrates, and the SFM predicted markedly higher extents of intestinal metabolism for oral over i.v. dosing. Thus, the SFM provides a physiological view of the intestine and explains the observation of route-dependent, intestinal metabolism.
    Drug Metabolism and Disposition 03/2000; 28(2):224-35. · 3.33 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. DOI:10.1097/00000539-199612000-00020 · 3.42 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. DOI:10.1097/00000539-199504000-00016 · 3.42 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. (Anesth Analg 1995;80:740-6)
    Anesthesia & Analgesia 01/1995; 80(4):740-746. DOI:10.1213/00000539-199504000-00016 · 3.42 Impact Factor
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    ABSTRACT: The effect of lyophilization on the physical characteristics of two different molecular mass hyaluronates (164 and 741 kDa) has been evaluated using dynamic oscillatory viscometry and size exclusion chromatography. The hyaluronates were prepared as either the free acid or the sodium salt. The reological and SEC profiles of sodium hyaluronate were not affected by lyophilization. In contrast, the complex viscosity and related dynamic moduli were markedly decreased after lyophilization of the hyaluronates in the free acid form. Size exclusion chromatography indicated a reduction in molecular mass of these samples. These data indicate that lyophilization of hyaluronates as the free acid, as opposed to a sodium salt form, can have a detrimental effect on their physical characteristics.
    International Journal of Pharmaceutics 10/1994; 111(3-111):205-211. DOI:10.1016/0378-5173(94)90342-5 · 3.79 Impact Factor
  • P J Hughes, M M Doherty, W N Charman
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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. · 1.47 Impact Factor