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D J Morgan

Publications and source records attributed to D J Morgan.

At least 127 records · Page 7Linked to original sources
PubMed1991

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver.

1. The effect of the erythrocyte stage of malaria infection on hepatic glucuronidation, biliary excretion and oxidation processes was investigated using harmol, salbutamol, taurocholate and propranolol. Livers from rats infected with the rodent malaria parasite P. berghei were isolated and perfused in a single-pass (harmol, taurocholate, propranolol) or recirculating (harmol, salbutamol) design. The degree of erythrocytic parasitaemia ranged from 16% to 63%. 2. The hepatic clearance (Cl) of harmol decreased from 7.8 +/- 0.4 ml/min in controls to 5.7 +/- 1.1 ml/min in the malaria-infected group in single-pass studies. This corresponded to a 40-60% reduction in hepatic intrinsic clearance (Clint). Similar changes were observed using the recirculating design when glucuronidation accounted for greater than 90% of harmol metabolism. 3. The Cl of salbutamol, metabolized exclusively by glucuronidation under the conditions used, also decreased significantly from 8.5 +/- 0.8 in controls to 6.6 +/- 1.4 ml/min in the malaria-infected group. This corresponded to a 40-70% reduction in Clint. 4. The Cl of taurocholate, excreted unchanged in bile, decreased slightly but significantly from 9.6 +/- 0.3 ml/min in controls to 8.3 +/- 0.9 ml/min in the malaria-infected group. In the same livers, there was also a slight but significant decrease in propranolol Cl (10.0 +/- 0.1 ml/min and 9.9 +/- 0.1 ml/min, respectively). Both these compounds undergo flow-limited hepatic clearance; the decreases in Clint of taurocholate and propranolol were 87% and 35%, respectively. 5. Cl and Clint of each of the compounds studied were found to correlate significantly with the degree of erythrocytic parasitaemia. This study shows that glucuronidation, biliary excretion and oxidation by liver are impaired in malaria infection in rats, with biliary excretion being the most affected. The data indicate that there is a general decrease in hepatic elimination processes during the erythrocytic phase of malaria infection.

Albuterol↗
PubMed1990

Kinetic assessment of apparent facilitation by albumin of cellular uptake of unbound ligands.

Previous studies of the effect of albumin on initial uptake of ligands by isolated cell suspensions or cultures found that the apparent uptake for unbound ligand appeared larger in the presence of binding to the albumin than when albumin was absent. Furthermore, when ligand and albumin were increased in a fixed molar ratio, uptake appeared to be competitively inhibited by the excess albumin. We examined the kinetics underlying this apparent facilitation phenomenon by incorporating unbound fraction of ligand in the medium (fu1) into the general model for diffusion between two compartments. The analysis showed that even in the absence of facilitation by albumin, the apparent rate constant for uptake of unbound ligand (k/fu1) increases as albumin concentration increases but the uptake clearance of unbound ligand remains constant. This theoretical analysis was verified experimentally by measuring the effect of albumin on uptake rates of 14C-taurocholate (12, 24, 48, 60, and 96 microM, with and without 0.87 mM albumin) in a nonphysiological system consisting of two solutions separated by a cellulose membrane. Moreover, when the taurocholate and albumin concentrations were increased in a fixed molar ratio of 0.06 (taurocholate 12-96 microM, albumin 0.2-1.6 mM), the initial uptake rate exhibited the same nonlinear pattern as the previous studies that used living cells. This pattern was due not to saturation of a putative albumin receptor but simply to the concomitant decrease in fu1 which tended to offset the increase in uptake rate due to the increasing total taurocholate concentration. The model was also used to evaluate published data describing the effect of albumin on the uptake of iopanoic acid by cultured hepatocytes. In accordance with the model, k1/fu1 increased as albumin concentration increased, but uptake clearance was independent of albumin concentration. Therefore, the kinetic pattern found in this and other studies with isolated cell suspensions or cultures argues against a special role for albumin in facilitating cellular ligand uptake.

Animals↗
PubMed1990

Review article: hypoxia and hepatic drug metabolism--clinical implications.

Most major pathways of hepatic drug metabolism are dependent on oxygen. Hepatic mixed-function oxidases use oxygen directly as a substrate, while many other enzyme systems are indirectly dependent on oxygen for the generation of essential co-factors, such as NAD+ and ATP. Studies in vitro show that many of these oxygen-dependent reactions are impaired by relatively minor reductions in oxygen supply, of a magnitude likely to be encountered in vivo. Phase I metabolism by mixed-function oxidases appears to be more sensitive to hypoxia than phase II drug conjugation, although the oxygen requirements of conjugation reactions, such as glucuronidation, may be greatly enhanced by poor nutrition or fasting. Studies in humans are few, but in general they affirm the potential importance of the effects of hypoxaemic states on hepatic drug elimination. On present evidence, special care should be taken in hypoxic patients with drugs extensively metabolized by the liver, particularly those which have a low therapeutic ratio.

Animals↗
PubMed1990

Pharmacokinetics of propofol when given by intravenous infusion.

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.

Adult↗
PubMed1990

Clinical significance of pharmacokinetic models of hepatic elimination.

Various pharmacokinetic models, both simple and complex, have been developed to describe the way in which the rate of hepatic elimination of drugs depends on hepatic blood flow, hepatic intrinsic clearance and unbound fraction of drug in blood. A model is necessary because it is not possible to measure the average blood concentration of drug within the liver, i.e. the concentration at the site of drug elimination. However, the predictions of these models can differ markedly for drugs of high hepatic clearance, especially with the oral route of administration. Investigations of the models have mostly involved studies with in vitro experimental preparations, such as isolated perfused livers. While such studies have advanced our understanding of the mechanism of hepatic uptake and elimination processes, the implications for clinical drug usage have been somewhat neglected. Use of one of the available models is necessary for the assessment of the capacity of in vivo hepatic drug metabolism processes (i.e. hepatic intrinsic clearance) and for predicting the effect of increasing dose on blood concentrations of high clearance drugs exhibiting Michaelis-Menten elimination kinetics, especially those that undergo a nonlinear hepatic first-pass effect. Clinically significant differences between the models can occur under these circumstances. A model is also required for quantitative prediction of the effect on blood drug concentrations of changes in hepatic blood flow, hepatic intrinsic clearance or drug-protein binding in blood. It is in predicting these changes that differences of major clinical significance can occur between the models. The greatest differences are seen in predicting the effect for orally administered drugs of changes of hepatic blood flow on blood concentrations, and changes of protein binding on unbound blood concentrations of drug. These changes can result from disease processes, altered physiology (old age or pregnancy), food intake or concomitant administration of other drugs. A model is also required for determining the mechanism by which such clinical changes occur. When considering these effects on hepatic elimination, it is essential to appreciate that the conclusions may depend markedly on the particular model chosen. Until more data on the applicability of the models are obtained in humans, the undistributed sinusoidal and venous equilibrium models, which represent the opposite extremes of behaviour among the available models, should both be used in assessing hepatic drug elimination.

Humans↗
PubMed1990

Clinical pharmacokinetics of beta-agonists.

The beta-agonists have found wide clinical use as racemic mixtures for 20 years, but information on their pharmacokinetics is not comprehensive. They are well absorbed orally, but have low systemic availability due to extensive first-pass sulphation. When administered by inhalation, very little of the administered dose reaches the lungs, but the small amount that does produces effective bronchodilatation. Plasma protein binding of most beta-agonists is negligible, and there is substantial extravascular distribution of the administered dose. Elimination of intravenous drug is predominantly renal, whereas oral doses are mostly eliminated by biotransformation. Renal clearance correlates with creatinine clearance; therefore, dose reduction should be considered if renal function is impaired, such as in the elderly or in cardiac failure. The elimination half-life of most beta-agonists is relatively short, and pharmacokinetics are independent of dose and duration of treatment. Differences in the pharmacokinetics of the enantiomers are evident. There is very large variation in pharmacodynamic response for a given plasma beta 2-agonist concentration among different subjects, and as treatment proceeds in an individual subject. Therefore, in most cases therapeutic response and side effects are more useful for the monitoring of beta 2-agonist treatment than measurement of plasma drug concentrations. The pharmacokinetics of beta 2-agonists are not greatly altered in pregnancy although these agents cause a marked reduction in maternal renal function. Placental transfer is relatively rapid, and side effects are observed in fetus and neonate. Elimination may be somewhat faster in children (8 to 15 years) than in young adults. Asthma does not appear to influence the pharmacokinetics of beta 2-agonists; the only recorded drug interaction of clinical significance is an increase in theophylline clearance by intravenous isoprenaline (isoproterenol). Controlled release oral preparations do not reduce side effects, but may improve compliance due to less frequent dosing. The application of pharmacokinetic principles may improve the clinical usage of beta-agonists, at least when they are used in premature labour and in cardiac failure.

Adolescent↗
PubMed1990

Ontogeny of fetal renal organic cation excretion: a study with cimetidine and ranitidine during the latter half of gestation in the pregnant ewe.

The organic cation cimetidine undergoes renal tubular secretion in the near-term ovine fetus. We investigated the ontogeny of renal tubular secretion of organic cations in the fetus from 80 days of gestation (term = 145). Sixteen sheep were administered both cimetidine and ranitidine in random order by a combination of bolus and i.v. infusion to achieve steady-state plasma concentrations of 1000 to 2000 ng/ml. A further two sheep received cimetidine only. Steady-state plasma concentrations were reached within 2 to 3 hr. Creatinine was used as a marker of glomerular filtration rate. Maternal renal clearance of cimetidine (0.51 +/- 0.18 l/min) and ranitidine (0.54 +/- 0.14 l/min) were not correlated with the period of gestation. Cimetidine/creatinine and ranitidine/creatinine renal clearance ratios were higher than unity being 5.48 +/- 1.91 and 5.65 +/- 1.18, respectively. Fetal creatinine renal clearance increased exponentially with gestational age (r2 = 0.577, P less than .001). Fetal renal clearance of both cimetidine and ranitidine also increased exponentially with gestational age, this trend being more clear-cut for cimetidine (r2 = 0.582, P less than .001) than for ranitidine (r2 = 0.254, P = .046). The rates of increase for cimetidine and ranitidine were similar to that for creatinine (P greater than .05). At 80 days, cimetidine/creatinine and ranitidine/creatinine renal clearance ratios (3.0 and 4.4, respectively) were higher than unity and did not increase further during the remainder of gestation. Therefore, the ovine fetus possesses an efficient tubular secretory pathway for organic cations by 80 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Oxygen dependence of salbutamol elimination by the isolated perfused rat liver.

Although impairment of drug metabolism by severe hypoxia is well documented in perfused liver preparations, the degree of hypoxia required to produce inhibition of drug elimination pathways in the intact liver has not been defined. In this study, in the isolated perfused rat liver, we examined the relationship between the rate of hepatic oxygen supply and the elimination rate of the drug salbutamol, which in the rat liver is eliminated largely by glucuronidation. Livers (N = 15) from male Sprague-Dawley rats were perfused in a non-recycling design with 10% human red cells in a Krebs-Henseleit electrolyte solution. Salbutamol elimination was examined during normal oxygenation (perfusate equilibrated with 100% O2; mean O2 delivery 3.21 mumol/min/g liver), at a given lower rate of oxygen delivery (achieved by producing different mixtures of N2 with O2 in the perfusate oxygenator) and after reoxygenation. In these experiments, hepatic clearance of salbutamol (perfusate concentration 50 ng/ml) was essentially independent of oxygen delivery above a rate of 2.0 mumol/min/g liver; below this level, clearance fell linearly as O2 supply was reduced. In all livers, reoxygenation restored drug elimination to control levels. In further experiments using a recycling design (N = 22), the effect of hypoxia on salbutamol elimination was found to be very similar. In recycling normoxic experiments (N = 3), the glucuronide metabolite was detected in perfusate and bile, but no sulphate metabolite was detected. While previous studies indicate that elimination of some oxidatively metabolised substrates is very sensitive to reductions in hepatic oxygenation, the present study shows that, in the isolated liver, large reductions in hepatic oxygen supply were required to produce significant impairment of the glucuronidation-dependent elimination of salbutamol.

Albuterol↗
PubMed1989

Permeability studies on protective gloves used in dental practice.

The recent guidelines issued by the DHSS and the BDS recommend that to prevent cross-infection gloves should be worn by dentists and their assistants whilst treating all patients. Little information is available on the permeability of the various types of glove available; this pilot study was therefore conducted, to test five commonly used brands of gloves for permeability to air, electrolytes, dye and bacteria. Tests were carried out before and after using the gloves for varying periods. From these studies it was found that only one brand of glove passed all the tests before wearing. After wearing the gloves for up to 3 hours, between 20% and 50% of the gloves, depending on type, allowed bacteria to pass across the glove. The visual test was less critical than the ion passage and bacterial tests, in that some gloves without obvious perforations allowed ions and bacteria to pass through.

Coloring Agents↗
PubMed1989

Prediction of acute myocardial disposition of antiarrhythmic drugs.

Using peripheral blood concentration and myocardial content data (from coronary sinus catheterization and serial determination of transmyocardial drug concentration gradients) from a previous clinical study of the antiarrhythmic drugs lidocaine and mexiletine, we tested the hypothesis that two prospectively defined models of myocardial drug disposition could be used to predict myocardial drug content, in the first 30 min following bolus iv injection, from peripheral blood concentrations alone. Compartmental analysis of peripheral blood concentration data from prolonged blood sampling (three-compartment model) and from the first 30 min after drug injection (two-compartment model) was used to calculate drug content, during the first 30 min, in the second compartment of each of the models. The time course of calculated compartmental content was similar to that of the measured myocardial content in 16 of the 18 patients studied, although there were some differences in the time of peak content. This relatively noninvasive method may therefore be useful in predicting the time course of myocardial drug content after acute iv drug administration.

Anti-Arrhythmia Agents↗
PubMed1989

Influence of unbound fraction and perfusate flow rate on taurocholate elimination by perfused rat liver: applicability of three distributed models.

The applicability of three different distributed models to the kinetics of elimination of taurocholate by isolated perfused rat liver was examined by fitting each model to literature data. Each of the models was able to predict the effect of changing hepatic blood flow on elimination, but only the model which incorporates separate density functions describing the degree of sinusoidal heterogeneity of blood flow and intrinsic clearance was able to predict the effect of changing unbound fraction on elimination.

Animals↗
PubMed1989

Oxygen dependence of omeprazole clearance and sulfone and sulfide metabolite formation in the isolated perfused rat liver.

Severe acute hypoxia is known to inhibit markedly the elimination of oxidatively metabolized drugs by the isolated liver. However, little is known of the degree of hypoxia required to produce inhibition of drug elimination by oxidative pathways in the intact organ. This study, in the isolated perfused rat liver, examined the oxygen dependence of the hepatic elimination of omeprazole, a drug which undergoes extensive oxidative metabolism in the rat. The relationship between hepatic oxygen supply and the production of omeprazole's oxidative sulfone and reductive sulfide metabolites was also examined. Rat livers were perfused at 15 ml/min with a perfusate containing 5 micrograms/ml of omeprazole in a single-pass design. Omeprazole clearance and the formation clearance of the two metabolites were measured in each liver during normal oxygenation, at different levels of hypoxia and after reoxygenation. There was a linear relationship between omeprazole clearance and oxygen delivery over the whole range studied. Production of the sulfone was similarly oxygen-dependent whereas the sulfide was only detectable after a significant reduction in oxygenation. In a further group of experiments the oxygen dependence of omeprazole clearance was shown to not be altered when the concentration of drug was lowered to 1 microgram/ml. This study shows that oxygen delivery is a critical determinant of the rate of oxidative drug metabolism in the isolated liver and supports the contention that reductions in hepatic oxygen supply may significantly alter the hepatic disposition of oxidatively metabolized drugs in vivo.

Animals↗
PubMed1989

Models of hepatic elimination: implications from studies of the simultaneous elimination of taurocholate and diazepam by isolated rat liver under varying conditions of binding.

Various kinetic models have been developed to describe the elimination of substances by the liver, but there is no agreement about which model is the most appropriate, as experimental evaluation is incomplete and results conflict. We have shown previously that hepatic elimination of taurocholate is best described by models that embody a high degree of sinusoidal heterogeneity or mixing, whereas another study showed that elimination of diazepam is best described by models that embody a low degree of sinusoidal heterogeneity or mixing. To investigate this discrepancy we examined, in the isolated perfused rat liver, the simultaneous elimination of taurocholate and diazepam. The effect on hepatic availability of varying unbound fraction (fu) in a single pass, steady-state system was studied in six experiments for taurocholate (fu, 0.066-0.966) and diazepam (fu, 0.051-0.675) by varying perfusate albumin concentration (0-60 g l-1). As before, elimination of taurocholate was best described by models that embody a high degree of sinusoidal heterogeneity or mixing (i.e., venous equilibrium model, dispersion model with dispersion number = infinity). Diazepam elimination was best described by models that embody a low degree of sinusoidal heterogeneity or mixing (undistributed sinusoidal model, dispersion model with low dispersion number = 1.04). A third model, a distributed model incorporating heterogeneity of sinusoidal blood flows and intrinsic clearances, fitted the data for both taurocholate and diazepam. The fitted coefficients of variation of both flow and intrinsic clearance among the sinusoids were large for taurocholate (176 and 164, respectively), but for diazepam blood flow was large (200) whereas that for intrinsic clearance was small (0.807).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Synergistic effects of hypoxia and fasting on harmol elimination in the isolated perfused rat liver.

In isolated hepatocytes the availability of intracellular glucose appears to be a key factor controlling the rate of xenobiotic glucuronidation during hypoxia. This study in the isolated perfused rat liver examines the effect of both a 24-hr fast and removal of glucose (8 mM) from liver perfusate on the elimination of bolus doses of harmol (20 mumol) under normoxic and hypoxic conditions. In the preparations used in these experiments, harmol glucuronide is the major metabolite (greater than 80%) with the remainder being sulphate. During normal oxygenation, in the livers from fed rats, harmol was rapidly eliminated (t1/2 = 4.2 +/- 0.4 min; mean +/- SD, N = 4). Fasting led to a small reduction in harmol elimination rate (t1/2 = 5.6 +/- 0.4 min; P less than 0.025) while removal of glucose from perfusate made no difference in either fed or fasted preparations. In the same livers, a second bolus dose of harmol was given during hypoxia. This produced a modest decline in harmol elimination in fed rats (t1/2 = 7.1 +/- 2.0 min; P less than 0.05). However, in fasted rats there was a striking reduction in harmol elimination (t1/2 = 109.8 +/- 54.0 min; P less than 0.025). The removal of glucose from perfusate made no significant difference to these results (t1/2 = 253 +/- 209 min in fasted preparations, P greater than 0.1). In all preparations, reoxygenation resulted in a rapid recovery of drug elimination. We conclude that nutritional state is important in determining the impact of hypoxia on harmol elimination by the liver. This study suggests that clinically significant reductions in xenobiotic glucuronidation are most likely to occur in poorly nourished or fasted subjects who became hypoxaemic.

Alkaloids↗
PubMed1988

Propranolol elimination as described by the venous equilibrium model using flow perturbations in the isolated perfused rat liver.

The kinetics of hepatic elimination of the high-clearance drug propranolol has been interpreted in a previous study from our laboratory, in which propranolol protein binding was varied, to conform to the venous equilibrium model. In another study by a different group, in which perfusate flow was varied, propranolol kinetics was interpreted to conform to the sinusoidal model. In the present study, we investigated the possibility that this discrepancy is due to the use of the two different discriminants, flow and protein binding, in the two studies. In eight livers, perfused in a recirculating design, steady-state elimination of propranolol (infused at a rate of 22.8 micrograms/min) was examined at perfusate flow rates of 16 and 32 mL/min. Hepatic outflow concentration was independent of perfusate flow rate, while the logarithmic average concentration was significantly lower at the higher flow. These data conform to the venous equilibrium model and are not consistent with the sinusoidal model. This shows that the outcome of these modeling experiments does not depend on the experimental approach used, and reaffirms that the venous equilibrium model is appropriate for propranolol under the conditions studied.

Animals↗