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R A Smallwood

Publications and source records attributed to R A Smallwood.

At least 19 recordsLinked to original sources
PubMed1992

Fasting increases the sensitivity of hepatic harmol glucuronidation to hypoxia.

Livers from fasted (N = 16) and fed (N = 22) rats were perfused with harmol (50 microM) for an initial 30 min with normal oxygen delivery (6-10 mumol/min/g liver), then for 45 min with perfusate equilibrated with O2/N2 mixtures, which reduced hepatic oxygen delivery to 0.9-6 mumol/min/g liver, and finally for a further 30 min period of normal oxygenation. Seventy per cent of the harmol eliminated was accounted for as the glucuronide conjugate and approximately 5% as the sulphate conjugate. During the hypoxia phase with fed preparations, decreasing oxygenation did not reduce harmol clearance or harmol glucuronide formation clearance until oxygen delivery was less than 2.5 mumol/min/g liver, whereas with fasted preparations this hypoxic threshold was much higher (5 mumol/min/g liver). Below the hypoxic threshold, harmol clearance was linearly related to oxygen delivery in both groups. Hepatic tissue concentrations of unchanged harmol at the end of the hypoxia phase were double those after the same period of normal oxygenation, whereas tissue harmol glucuronide concentrations were similar. By establishing a hypoxic threshold for reduced oxygen availability this study shows that harmol glucuronidation is relatively insensitive to hypoxia, but sensitivity increases markedly in fasted animals.

Animals↗
PubMed1992

Effect of malaria on phenol conjugation pathways in perfused rat liver.

The effect of malaria infection (MI) on sulphation and glucuronidation of phenol was investigated in single-pass perfused livers from rats infected with the rodent malaria parasite Plasmodium berghei. At a hepatic inflow (Cin) phenol concentration of 1 microgram/mL in controls, 52% was metabolized to sulphate conjugate and 37% to glucuronide conjugate at steady state. At this Cin, MI had no effect on phenol clearance (CL) (control: 9.63 +/- 0.38 vs MI: 9.65 +/- 0.36 mL/min; P greater than 0.05) or on the formation clearance (CLm) of the glucuronide or sulphate conjugates of phenol. When phenol Cin was increased 10-fold to 10 micrograms/mL, 6% was metabolized to sulphate conjugate and 94% to glucuronide conjugate. At this Cin phenol CL was decreased significantly (control: 9.44 +/- 0.46 vs MI: 7.09 +/- 1.51 mL/min; P less than 0.05) and represented a decrease in intrinsic clearance (sinusoidal perfusion model) of at least 55%. This decrease was accounted for entirely by the decrease in the CLm of the glucuronide conjugate (control: 8.88 +/- 0.96 vs 5.98 +/- 1.87 mL/min; P less than 0.05), whereas the CLm of the sulphate conjugate was unchanged. There was a negative correlation between phenol glucuronide CLm and the severity of the erythrocytic parasitaemia (r2 = 0.75, P less than 0.05). The dose-dependent reduction in phenol glucuronidation in MI may be due to reduced availability of the cosubstrate uridine diphosphoglucuronic acid (UDPGA), because previous studies have shown that UDPGA availability depends on glycogen stores, which are known to be reduced in MI. These data suggest that sulphate conjugation is preserved in MI and that glucuronidation is preserved at low doses of substrate. At high substrate doses, glucuronidation is impaired in MI and the impairment correlates with the severity of the infection.

Animals↗
PubMed1992

High-performance liquid chromatographic method to resolve and determine lipopolysaccharide sub-groups of Escherichia coli endotoxin in isolated perfused rat liver perfusate.

A high-performance liquid chromatographic method was developed for resolving heterogeneous preparations of fluorescently labelled endotoxin derived from Escherichia coli (Serotype 0111:B4) into separate lipopolysaccharide sub-groups. The endotoxin was chromatographed on an analytical gel permeation column using a mobile phase of acetonitrile (20%, v/v) and 100 mM phosphate buffer (pH 7.75). Four fluorescent peaks were resolved, representing sub-groups of markedly different molecular sizes. Three of the four sub-groups contained the core polysaccharide 2-keto-3-deoxyoctonate, confirming that they contained lipopolysaccharide. Fluorescein isothiocyanate (FITC)-labelled endotoxins derived from Vibrio cholerae and Salmonella minnesota chromatographed using the same system eluted with distinctly different patterns of peaks from each other and from E. coli. Extraction of E. coli FITC-endotoxin from a buffer solution using a phenol-diethyl ether method and subsequent chromatography allowed the determination of three of the four fluorescent sub-groups over the concentration range 1-15 micrograms/ml.

Animals↗
PubMed1992

Ageing has no effect on the volume density of hepatocytes, reticulo-endothelial cells or the extracellular space in livers of female Sprague-Dawley rats.

1. The hepatic reticulo-endothelial cell population is generally assumed to increase in size, along with the liver, during ageing in rats. However, this has not been rigorously established. 2. Using electron microscopy and stereological techniques, the present study has shown that the volume densities of hepatocytes and Kupffer cells (and probably also of endothelial cells, fat storing cells and the extracellular space) of the livers of female Sprague-Dawley rats are the same at 2 and 24-25 months of age. 3. This result indicates that the increase in size of the liver during ageing in the rat is associated with an equivalent increase in the volume of each cell population and the extracellular space.

Aging↗
PubMed1991

Augmentin-induced jaundice.

OBJECTIVE: To alert clinicians to the hepatotoxic potential of Augmentin (amoxycillin and clavulanic acid), a widely prescribed antibiotic, in susceptible patients, and to point out that the hepatic illness may be delayed but serious and protracted. DESIGN AND SETTING: Case reports of patients with Augmentin-induced jaundice referred to the gastroenterology departments in three major teaching hospitals, and a review of cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). PATIENTS: Eight patients with nine episodes of Augmentin-induced jaundice personally treated by the authors from March 1988 to February 1990 are described. A further 19 patients reported to ADRAC from May 1987 to November 1989 are discussed. All patient histories were carefully reviewed to ensure that there was a temporal relationship between the course of Augmentin and the onset of the hepatitic illness and that other causes of jaundice were reasonably excluded. RESULTS: Jaundice developed in some of these patients several weeks after drug treatment was completed. The illness may be protracted over many weeks. As yet, there has been no case of progressive disease leading to the liver failure. CONCLUSIONS: The data suggest that a hypersensitivity reaction to clavulanic acid is the likely cause of the jaundice. Therefore, Augmentin, although an important antibiotic, should be reserved for severe infections for which amoxycillin is unsuitable.

Adult↗
PubMed1991

Disposition of the diastereoisomers quinine and quinidine in the ovine fetus.

The disposition of the diastereoisomers quinine and quinidine was investigated in the near-term pregnant ewe. Five sheep were administered quinine and quinidine separately in random order by a combination of bolus and 30-h iv infusion. On a subsequent occasion, four of the five sheep were also administered the two drugs simultaneously. After separate dosage, systemic clearance of quinine tended to be greater than that of quinidine (714 +/- 299 versus 422 +/- 146 mL/min, p = 0.08). Maternal renal clearance exhibited no stereoselectivity and represented less than 2% of total clearance. Simultaneous administration did not alter the disposition of either drug in the mother. After separate dosage, fetal total concentrations (Cf) of quinine and quinidine were substantially lower than maternal total concentrations, as reflected in Cf:Cm ratios of 0.15 +/- 0.06 versus 0.10 +/- 0.08, respectively. Similarly, fetal unbound concentrations (Cfu) were substantially lower than maternal unbound concentrations (Cmu; Cfu/Cmu = 0.46 +/- 0.09 for quinine and 0.23 +/- 0.09 for quinidine). This indicates the presence of fetal elimination of both isomers. Fetal renal clearances of quinine and quinidine were similar (0.34 +/- 0.24 mL/min versus 0.38 +/- 0.24 mL/min) and less than that of endogenous creatinine, indicating the absence of net renal tubular secretion. After simultaneous dosage of quinine and quinidine, Cf:Cm (0.48 +/- 0.24 and 0.31 +/- 0.19, respectively) and Cfu:Cmu (0.73 +/- 0.14 and 0.52 +/- 0.20, respectively) were greater than for separate dosages. Fetal renal clearance of both drugs was unchanged, suggesting that the higher Cfu:Cmu ratios after simultaneous dosage were due to mutual inhibition of the fetal metabolism of these drugs.

Animals↗
PubMed1991

Quinidine single dose pharmacokinetics and pharmacodynamics are unaltered by omeprazole.

Omeprazole has been shown in previous studies to inhibit the hepatic metabolism of selected drugs. Quinidine is an antiarrhythmic and antimalarial agent with a low therapeutic index. We therefore examined the effect of 40 mg omeprazole daily for one week or placebo on the pharmacokinetics and pharmacodynamics of a single 400 mg dose of quinidine in 8 healthy volunteers in a double-blind crossover study. During placebo and omeprazole treatment, there was no significant difference in area under the time-plasma quinidine concentration curve, (17.0 +/- 4.83 micrograms.h/ml, 18.6 +/- 4.43 micrograms.h/ml, respectively; P greater than 0.2) or renal clearance of quinidine (56.2 +/- 26.0 ml/min, 55.6 +/- 12.7 ml/min, respectively; P greater than 0.5). Quinidine unbound fraction in plasma (0.170 +/- 0.041 vs. 0.166 +/- 0.041 in the presence of omeprazole; P greater than 0.5) was not altered by omeprazole. Peak plasma quinidine concentration and the time this occurred did not differ. Omeprazole also had no effect on these parameters for the metabolite 3-hydroxyquinidine. There was no significant difference in the change in the corrected Q-T interval on the electrocardiogram due to quinidine (mean area under the time versus delta Q-Tc curve = 351 +/- 192 ms.h, placebo; 414 +/- 303 ms.h, omeprazole) showing that quinidine pharmacodynamics were unaltered by omeprazole. We conclude that omeprazole does not affect the pharmacokinetics of quinidine.

Adult↗
PubMed1991

Oral bioavailability of omeprazole before and after chronic therapy in patients with duodenal ulcer.

1. This study investigated the mechanism of the increase in oral bioavailability of omeprazole during repeated oral dosing. Eight patients with duodenal ulcer received an i.v. dose of omeprazole before and after a 4-week course of oral omeprazole, 20 mg daily, given as enteric-coated granules. 2. AUCoral and oral bioavailability (F) increased during omeprazole treatment by 50% (P less than 0.01) and 35% (P less than 0.05), respectively. 3. There was no change in the systemic clearance of omeprazole after i.v. dosage following the course of treatment. 4. We conclude that the increased omeprazole AUC observed on repeated administration of enteric-coated granules is due to increased systemic availability rather than decreased systemic elimination. The increased availability appears to be due to increased gastrointestinal absorption rather than decreased first-pass hepatic extraction.

Administration, Oral↗
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

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine.

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.

Adult↗
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

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

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↗