Variability of the blood/plasma concentration ratio of pethidine.
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Humans↗
Biomedical subjects
D J Morgan
Publications and source records attributed to D J Morgan.
Placental transfer of omeprazole in maternal and fetal sheep.
The placental transfer of omeprazole was studied over a 4-fold dose range in 7 nonanesthetized near-term pregnant sheep. There was a 5 to 1 maternal to fetal transplacental gradient of steady-state total omeprazole concentrations after both low dose (maternal plasma 556 +/- 361 ng/ml, fetal plasma 101 +/- 57 ng/ml) and high dose (maternal plasma 2,660 +/- 1,130 ng/ml, fetal plasma 563 +/- 182 ng/ml). Although this was in part due to differences in plasma protein binding between mother (unbound fraction 6.6 +/- 5.5%) and fetus (unbound fraction 11.9 +/- 2.4%), a 2 to 1 maternal to fetal gradient of steady-state unbound omeprazole concentration was still present (144 +/- 73 ng/ml vs. 64 +/- 32 ng/ml). Fetal omeprazole total plasma concentrations correlated strongly with maternal total drug concentrations (r = 0.84, p less than 0.025) and with the inverse of maternal omeprazole total systemic clearance (r = 0.77, p less than 0.05), indicating that maternal drug disposition was a major determinant of fetal omeprazole plasma concentrations. Urinary clearance of omeprazole was low in both mother (0.137 +/- 0.046 ml/min) and fetus (0.067 +/- 0.039 ml/min). This study demonstrates that the fetus is exposed to about one half of the unbound omeprazole concentration in maternal plasma and suggests that the extent of fetal exposure is largely dictated by maternal drug distribution and elimination characteristics.
Animals↗
Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.
Determination of short-term myocardial drug uptake and subsequent redistribution was performed in 27 patients with ischemic heart disease for the antiarrhythmic agents lidocaine and mexiletine, using frequent simultaneous measurements of drug concentration in aortic and coronary sinus blood, combined with measurement of coronary sinus blood flow after intravenous bolus injection of the drug. Maximal myocardial drug content per unit resting coronary sinus blood flow (MDC:F) was significantly greater in patients in whom coronary sinus pacing at 100 beat/min was performed during the initial period of drug uptake. Maximal myocardial drug content occurred after 2.4 +/- 0.2 (SEM) for lidocaine and after 5.5 +/- 0.6 min for mexiletine (p less than .001), and pacing did not affect time to maximum myocardial drug content. In nonpaced, but not paced, patients maximal MDC:F was greater in the lidocaine group than that in the mexiletine group. The subsequent efflux of lidocaine from the myocardium was more rapid that that of mexiletine in both paced and nonpaced groups.
Adult↗
Effect of hypoxia on oxidative and reductive pathways of omeprazole metabolism by the isolated perfused rat liver.
The effect of hypoxia on the elimination of omeprazole, a potent inhibitor of gastric acid secretion, was studied in the isolated perfused rat liver. During normal oxygenation, a 10 mg bolus dose was eliminated rapidly (T 1/2 beta = 8.0 +/- 1.1 min; mean +/- S.E.M., N = 4), while under hypoxic conditions T 1/2 beta was increased to 81.6 +/- 5.4 min (P less than 0.01). Upon reoxygenation, T 1/2 beta returned to 9.6 +/- 1.3 min. During hypoxia, perfusate concentrations of an oxidative metabolite (the sulphone) were reduced by 68%, while those of the reductively-generated sulphide increased 4-fold. With reoxygenation, both formation and elimination of the sulphone were increased, while the sulphide, which had accumulated during the hypoxic period, was eliminated rapidly. These findings were duplicated in steady-state experiments, in which omeprazole clearance during hypoxia fell by at least 70%, and sulphide concentrations in perfusate rose from undetectable levels to 200 ng/ml (at least a 10-fold increase). Sulphone concentrations did not change with hypoxia, consistent with a reduction in both its formation and elimination rates. We conclude that the hepatic elimination of omeprazole is severely retarded by hypoxia, but that this effect is promptly reversed by reoxygenation. The increased formation of reductive metabolite during hypoxia is not of sufficient magnitude to sustain the normal hepatic elimination of omeprazole.
Animals↗
Variation in hepatic extraction ratio with unbound drug fraction: discrimination between models of hepatic drug elimination.
Systematic examination of model-dependent predictions of changes in the hepatic extraction ratio (E), following alteration in the unbound fraction of drug in plasma (fub), should allow sensitive discrimination between the venous equilibrium model (model I) and the sinusoidal perfusion model (model II) of hepatic sinusoidal function if drugs which show high clearance of free drug are used. Analysis of experimental data from the literature confirmed the utility of this approach. Specifically, data related to diazepam (E = 0.95 at fub = 1) clearly conformed to the predictions of the sinusoidal perfusion model and differed markedly from those of the venous equilibrium model. Conversely, data for phenytoin (E = 0.69 at fub = 1) failed to discriminate between models, as predicted by our analysis. We identify a sensitive, convenient method for discrimination between current models of hepatic sinusoidal function and establish for the first time that a drug substrate (diazepam) conforms closely to the predictions of the sinusoidal perfusion model.
Diazepam↗
Evaluation of infusion regimens for thiopentone as a primary anaesthetic agent.
Several multi-stage infusion regimens and a computer controlled exponentially decreasing infusion regimen were evaluated in twelve patients undergoing head and neck surgery or neurosurgery. Thiopentone dosage was based on the mean of pharmacokinetic parameter values from the literature and adjusted for each patient's lean body mass in order to rapidly achieve a predetermined plasma thiopentone concentration of 15 or 20 micrograms/ml in the period following the initial bolus dose to induce anaesthesia. Anaesthesia was satisfactory in all cases. Plasma thiopentone concentrations were maintained between 10-20 micrograms/ml during infusion in the five patients who received either a four or five stage infusion and in the six patients who received the exponential infusion, but not in the single patient who received a two-stage infusion. The mean recovery time was 111 min. The plasma concentrations of total and unbound thiopentone at awakening showed little intersubject variability, despite considerable differences in total dose and duration of infusion, suggesting the absence of acute tolerance to the drug. Plasma clearance of total thiopentone correlated strongly with calculated lean body mass and to a lesser extent with total body weight suggesting that lean body mass, in particular, should be an accurate predictor of thiopentone maintenance dose requirements. This study shows that it is feasible to use thiopentone as a primary anaesthetic agent during surgery by administering the drug either as an exponentially decreasing infusion or as an infusion comprising 4 or 5 stepwise decreasing rates.
Adolescent↗
Circulating histamine and neutrophil chemotactic activity during allergen-induced asthma: the effect of inhaled antihistamines and anti-allergic compounds.
Plasma histamine and serum neutrophil chemotactic activity (S-NCA) were measured in ten atopic asthmatic patients on four separate occasions after allergen bronchial provocation testing (BPT). Single doses of inhaled sodium cromoglycate (SCG; 20 mg), clemastine (0.5 mg), ketotifen (0.5 mg) and isotonic saline (0.9% NaCl) placebo were administered 30 min before bronchial provocation testing in random order and double-blind. The airflow obstruction after BPT was monitored by measurement of forced expiratory volume in 1 s (FEV1). Plasma histamine was measured by the double-isotope radioenzymatic assay and S-NCA by a modified Boyden chamber technique. A highly significant decrease in FEV1 after BPT occurred on the placebo pre-treatment visit (P less than 0.001). Prior administration of inhaled SCG, clemastine and ketotifen significantly reduced the decrease in airflow obstruction seen after BPT when compared with placebo treatment (P less than 0.01, P less than 0.02, P less than 0.05 respectively). No significant alteration in plasma histamine was detected during allergen-induced airflow obstruction. Levels of S-NCA were significantly higher 5, 10 and 15 min after BPT when compared with the pre-challenge level (P less than 0.01, P less than 0.01, P less than 0.001 respectively). These levels were not significantly decreased when airflow obstruction was inhibited by the prior inhalation of SCG, clemastine or ketotifen.
Adult↗
Pentobarbitone formation during thiopentone infusion.
The plasma concentrations and elimination half-life of pentobarbitone were determined in 14 surgical patients receiving a continuous, exponentially decreasing, infusion of thiopentone (mean total dose, 1.05 g; SD 0.34; mean duration of infusion 2.4 hours, SD 0.7) as the primary anaesthetic agent. The plasma pentobarbitone concentration increased gradually, to reach a maximum of 1.49 micrograms/ml (SD 0.61) at the end of the thiopentone infusion, which was 15.5 per cent (SD 6.04) of the plasma thiopentone concentration. The elimination half-life of pentobarbitone measured over the following 70 hours in nine of the patients was 34.3 hours (SD 8.2), which is within the range of values reported previously in several studies in which pentobarbitone was administered directly to volunteers. It was concluded that the formation of this active metabolite during 2-3 hour thiopentone infusions was unlikely to be of clinical relevance, but that significant concentrations may occur with longer thiopentone infusions.
Adolescent↗
Influence of chronic dosing on theophylline clearance.
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Half-Life↗
The inhibitory effects of ranitidine and cimetidine on propranolol elimination by the rat isolated perfused liver.
The effect of low (50 micrograms) and high (1 mg) doses of the histamine H2-receptor antagonists cimetidine and ranitidine on the first pass extraction of propranolol was studied in the rat isolated perfused liver. Both low and high dose cimetidine increased the area under the perfusate propranolol concentration time curve (AUC) 4 to 5-fold. Although low dose ranitidine did not alter propranolol AUC, high dose ranitidine increased it to the same extent as cimetidine. These results indicate that ranitidine has a clear propensity for microsomal inhibition, but one which is unlikely to be manifest at therapeutic dosage.
Animals↗
Fetal exposure to cimetidine following chronic administration to pregnant sheep.
Our previous short term studies of the placental transfer of cimetidine in the pregnant sheep showed that following infusion of cimetidine to the mother, there was a striking (greater than 25 to 1) maternal to fetal gradient at apparent steady state. The present study examines two possible explanations: 1. That the gradient reflects very low placental permeability to cimetidine, such that in short-term studies a true steady state is not achieved. 2. That the gradient results at least in part from differences in protein binding in maternal and fetal plasma. To determine whether the gradient was due to very low placental permeability to cimetidine, pregnant sheep were infused with cimetidine continuously for 6 days (n=5). The large 25 to 1 cimetidine gradient did not diminish throughout this period, thereby ruling out a non-specific "barrier" effect of the placenta. In vitro protein binding studies of cimetidine in maternal and fetal plasma showed low binding (range = 16 to 46%) and minimal differences between mother and fetus. We conclude that the observed maternal to fetal cimetidine gradient cannot be explained by either low placental permeability, or by differential protein binding of cimetidine in maternal and fetal plasma.
Animals↗
Aortocaval compression and plasma concentrations of thiopentone at caesarean section.
The venous plasma concentration-time profiles of thiopentone were measured simultaneously over the first 30-40 min after induction of anaesthesia, in blood obtained from an arm vein and a vein in the foot, in nine healthy full-term women undergoing Caesarean section. Patients were tilted laterally to the left by from 8 to 18 degrees during the procedure. In all but two of the patients, the profiles from the arm and foot were virtually identical, suggesting that aortocaval compression was absent or insignificant. Therefore, the large intersubject variability in volume of distribution of thiopentone at Caesarean section is unlikely to be the result of aortocaval compression.
Adult↗
Pethidine binding in whole blood: methodology and clinical significance.
A three-compartment equilibrium dialysis method was developed for the simultaneous and direct determination of drug binding in whole blood and in plasma and of the blood to plasma concentration ratio (b/p). The unbound fraction of pethidine in the blood of six healthy volunteers (0.63, s.d. 0.09, n = 23 determinations) was significantly different from that in the blood of six patients (0.72, s.d. 0.08, n = 24 determinations). There was no significant difference in the b/p of six patients (0.84, s.d. 0.09, n = 24 determinations) and six volunteers (0.90, s.d. 0.14, n = 23 determinations). The observed unbound fraction of pethidine in blood (0.6 to 0.7) was considerably lower than previously reported. As this value for the unbound fraction (0.6 to 0.7) is similar to the reported estimated hepatic extraction ratio of the drug in man, it is proposed that pethidine elimination should be described as 'capacity limited, binding sensitive' rather than 'flow-limited'.
Adult↗
Pethidine binding in plasma: effects of methodological variables.
Several methodological variables potentially influencing the plasma protein binding of [14C]-pethidine in vitro were investigated using equilibrium dialysis and rigorous pH control. Ionic strength of buffer, pethidine concentration and 21 days of plasma samples frozen to -8 degrees C did not affect the outcome of the binding experiments. Unbound fraction decreased with increasing temperatures between 25 degrees C and 37 degrees C. Unbound fraction decreased with increased pH between pH 7.0 and 8.0; the mean unbound fraction at an equilibrium pH of 7.4 and at 37 degrees C was 0.58 (s.d. 0.03, n = 58). It is likely that previous reports of pethidine unbound fraction as being between 0.2 and 0.4 represent artefacts caused by inadequate pH control during dialysis.
Blood Proteins↗
Influence of chronic dosing on theophylline clearance.
Theophylline clearance was studied in normal healthy volunteers before and after chronic oral dosing. Oral theophylline clearance showed a significant decrease (P less than 0.001) from 59.3 +/- 6.48 ml/min (mean +/- s.e. mean, n = 10) to 48.0 +/- 6.4 ml/min. Steady-state intravenous clearance decreased by 26 +/- 2% from 55.1 +/- 7.7 ml/min to 41.0 +/- 5.96 ml/min (mean +/- s.e. mean, n = 6; P less than 0.001) at constant steady-state intravenous test concentrations (mean 15.0 +/- 1.6 micrograms/ml after chronic oral dosing), excluding significant concentration dependence. Extrapolation of acute clearance findings to maintenance requirement may not be valid even in the same individual, with theophylline therapy requiring on-going review beyond acute stabilisation.
Administration, Oral↗
A comparison of the available methods for the measurement of histamine in sputum.
Sputum samples from patients with chronic bronchitis were assayed for histamine content using a bioassay, and/or fluorometric assay and single or double radioenzymatic techniques. Comparison showed that all the assays produced significant differences in the measurement of sputum histamine. Similarly, it was observed that the assays all showed significant differences in the measurement of histamine released from human basophils. In general the fluorometric assay give the highest values for histamine in sputum and the double-isotope radioenzymatic assay the lowest. In contrast, no differences were found between the bioassay, fluorometric assay and the single-isotope radioenzymatic assay for the measurement of histamine added to Tyrode's solution. These results suggest that in biological samples some of the assays may additionally be measuring metabolites of histamine or other components present in the samples and underline the need to measure the levels of histamine and its metabolites separately in sputum.
Albuterol↗
Discrimination between the venous equilibrium and sinusoidal models of hepatic drug elimination in the isolated perfused rat liver by perturbation of propranolol protein binding.
To discriminate between two widely used models of hepatic drug elimination, the venous equilibrium and sinusoidal models, we examined the effect of altering perfusate protein binding on the hepatic elimination of the highly cleared drug, propranolol, by the isolated perfused rat liver. We investigated specifically the relationship between the unbound fraction of drug perfusing the liver and the steady-state unbound drug concentration in hepatic venous effluent (i.e., in the perfusate reservoir) after a constant infusion of drug (1.37 mg/hr) into the portal vein. Each rat liver (n = 21) was perfused over 60 min at one of seven different protein concentrations, such that the unbound fraction of propranolol in the portal venous perfusate was varied from 0.1 to 0.65. The unbound steady-state propranolol concentration in the hepatic venous effluent remained unchanged, despite an almost 7-fold increase in the free fraction of propranolol perfusing the liver. The data conform precisely to the predictions of the venous equilibrium model and are incompatible with the sinusoidal model, which predicts a 100-fold decrease in unbound reservoir concentration. This study therefore establishes that the apparently "unphysiological" venous equilibrium model represents a valid description of the hepatic elimination of this high clearance compound.
Animals↗
Determination of salbutamol in plasma by high-performance liquid chromatography with fluorescence detection.
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Albuterol↗