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G D Mellick

Publications and source records attributed to G D Mellick.

26 records · Page 2Linked to original sources
PubMed1998

Focused antithrombotic therapy: novel anti-platelet salicylates with reduced ulcerogenic potential and higher first-pass detoxification than aspirin in rats.

The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicylic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane A2 production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.

Animals↗
PubMed1998

Hepatic disposition and metabolite kinetics of a homologous series of diflunisal esters.

The hepatic disposition and metabolite kinetics of a homologous series of diflunisal O-acyl esters (acetyl, butanoyl, pentanoyl, and hexanoyl) were determined using a single-pass perfused in situ rat liver preparation. The experiments were conducted using 2% BSA Krebs-Henseleit buffer (pH 7.4), and perfusions were performed at 30 mL/min in each liver. O-Acyl esters of diflunisal and pregenerated diflunisal were injected separately into the portal vein. The venous outflow samples containing the esters and metabolite diflunisal were analyzed by high performance liquid chromatography (HPLC). The normalized outflow concentration-time profiles for each parent ester and the formed metabolite, diflunisal, were analyzed using statistical moments analysis and the two-compartment dispersion model. Data (presented as mean +/- standard error for triplicate experiments) was compared using ANOVA repeated measures, significance level P < 0.05. The hepatic availability (AUC'), the fraction of the injected dose recovered in the outflowing perfusate, for O-acetyldiflunisal (C2D = 0.21 +/- 0.03) was significantly lower than the other esters (0.34-0.38). However, RN/fu, the removal efficiency number RN divided by the unbound fraction in perfusate fu, which represents the removal efficiency of unbound ester by the liver, was significantly higher for the most lipophilic ester (O-hexanoyldiflunisal, C6D = 16.50 +/- 0.22) compared to the other members of the series (9.57 to 11.17). The most lipophilic ester, C6D, had the largest permeability surface area (PS) product (94.52 +/- 38.20 mL min-1 g-1 liver) and tissue distribution value VT (35. 62 +/- 11.33 mL g-1 liver) in this series. The MTT of these O-acyl esters of diflunisal were not significantly different from one another. However, the metabolite diflunisal MTTs tended to increase with the increase in the parent ester lipophilicity (11.41 +/- 2.19 s for C2D to 38.63 +/- 9.81 s for C6D). The two-compartment dispersion model equations adequately described the outflow profiles for the parent esters and the metabolite diflunisal formed from the O-acyl esters of diflunisal in the liver.

Algorithms↗
PubMed1998

Hepatic structure-pharmacokinetic relationships: the hepatic disposition and metabolite kinetics of a homologous series of O-acyl derivatives of salicylic acid.

1. The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-situ rat liver preparation. 2. The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3. Pregenerated SA ([14C]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4. The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5. The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6. The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUC', MTT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7. The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

Animals↗
PubMed1998

The effect of protein binding on the hepatic first pass of O-acyl salicylate derivatives in the rat.

In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mL min(-1) with perfusate albumin concentrations of 0, 2, and 4% w/v. The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (RN) of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (fu) of the esters decreased with lipophilicity. RN/fu for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, RN/fu for n-pentanoyl- and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%. Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.

Animals↗
PubMed1997

Metabolite mean transit times in the liver as predicted by various models of hepatic elimination.

Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver. Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tanks-in-series models are between the predictions of the tank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MTT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.

Animals↗
PubMed1997

Impulse-response studies on tracer doses of [14C]lignocaine and its multiple metabolites in the perfused rat liver.

The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [14C]lignocaine into the perfused rat liver. Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min-1 were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total 14C radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate << influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mL min-1 or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 microM unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content. The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the wellstirred model. The increase in lignocaine availability when 1200 microM unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.

Anesthetics, Local↗
PubMed1996

The disposition of aspirin and salicylic acid in the isolated perfused rat liver: the effect of normal and retrograde flow on availability and mean transit time.

The effect of changing the direction of perfusate flow from anterograde to retrograde on the disposition of acetylsalicylic acid (aspirin) and salicylic acid was studied in the single pass in-situ perfused rat liver. Mixtures of aspirin, [14C]salicylic acid and the inert reference solute [3H]sucrose were administered as boluses into the liver using red blood cell and albumin-free perfusate media at a flow rate of 30 mL min-1/liver. Hepatic availability (F), mean transit time (MTT) and normalized variance (CV2) for aspirin, preformed [14C]salicylic acid, salicylic acid produced from aspirin in the liver and [3H]sucrose were deduced from the outflow concentration profiles using statistical moment analysis. The values for F, MTT and CV2 for the solutes under anterograde perfusion were: aspirin (0.73 +/- 0.04, 15.13 +/- 2.01 s, 0.33 +/- 0.09, n = 5), preformed [14C]salicylic acid (1.05 +/- 0.06, n = 12, 43.19 +/- 2.21 s, 1.08 +/- 0.08, n = 5), salicylic acid from aspirin (0.33 +/- 0.05, 42.82 +/- 9.16 s, 0.73 +/- 0.10, n = 5) and [3H]sucrose (1.05 +/- 0.05, 16.88 +/- 0.77 s, 0.74 +/- 0.10, n = 5). The corresponding values for retrograde perfusions were: aspirin (0.73 +/- 0.02, 17.41 +/- 3.06 s, 0.32 +/- 0.09, n = 5), preformed [14C]salicylic acid (1.14 +/- 0.02, 44.42 +/- 3.16 s, 0.95 +/- 0.07, n = 5), salicylic acid from aspirin (0.33 +/- 0.09, 36.47 +/- 10.28 s, 0.58 +/- 0.05, n = 5) and sucrose (1.01 +/- 0.04, 18.08 +/- 1.61 s, 0.76 +/- 0.15, n = 5). No significant differences in F or MTT were apparent between anterograde and retrograde perfusions for all solutes. The MTT and CV2 data for [14C]salicylic acid and salicylic acid produced from aspirin is suggestive of a permeability limitation for salicylic acid transport.

Animals↗