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Biomedical subjects

D J Morgan

Publications and source records attributed to D J Morgan.

At least 145 records · Page 8Linked to original sources
PubMed1988

Influence of maternal plasma protein binding on fetal unbound plasma concentration of propranolol in the pregnant ewe.

According to theory, for a drug of nonrestrictive, flow-limited clearance, a change during pregnancy of the unbound fraction (fu) of drug in maternal plasma should cause a change in steady-state unbound plasma drug concentration (Cu) in maternal plasma, which should also cause a change in fetal Cu. This theory was examined in 14 chronically cannulated, unanesthetized pregnant ewes in which 28 separate experiments were performed during the latter part of gestation. An initial bolus dose and 3-h constant rate infusion of propranolol were administered via the maternal jugular vein and steady-state maternal and fetal carotid arterial plasma total and unbound propranolol concentrations were measured. Fetal Cu (32 +/- 21 ng/mL) was significantly less than maternal Cu (78 +/- 52 ng/mL), due to previously demonstrated fetal hepatic extraction of propranolol. Notwithstanding fetal elimination, there was a significant correlation between fetal Cu and maternal Cu (r = 0.41, p less than 0.025). There was also a strong correlation between fetal Cu and the maternal unbound fraction of drug (fu; r = 0.75, p less than 0.001). We conclude that for propranolol, a drug of nonrestrictive, flow-limited clearance, changes in maternal fu can have a significant influence on fetal Cu, and therefore would be expected to influence the pharmacological effect of the drug in the fetus.

Animals↗
PubMed1988

The effect of cardiopulmonary bypass on plasma protein binding of alfentanil.

The effect of cardiopulmonary bypass (CPB) on plasma concentration and protein binding of alfentanil was studied during continuous infusions in five cardiac surgical patients. Patients were given a loading infusion of 10 micrograms.min-1.kg-1 lean body mass (LBM) over 30 s followed by a fixed rate maintenance infusion of 1 microgram.min-1.kg-1 LBM for the duration of surgery. Prior to the commencement of CPB the total plasma alfentanil concentration was 177 micrograms.l-1. This fell to 92 micrograms.l-1 2 min after commencement of CPB and rose to 155 micrograms.l-1 at the end of CPB 2.01 h later. During the same period the unbound fraction of alfentanil rose from 0.16 to 0.35 two min after the start of CPB and fell gradually to 0.22 at the end of CPB. The unbound concentration prior to CPB was 29 micrograms.l-1 and was essentially unchanged by the onset of CPB, being 35 micrograms.l-1 at two min and then 31 micrograms.l-1 at the end of CPB. There was a good correlation between alfentanil bound/unbound concentration ratio and plasma albumin concentration (r = 0.57) and plasma alpha 1-acid glycoprotein concentration (r = 0.80), indicating that the decrease in binding during CPB was due primarily to haemodilution. In assessing the effects of CPB on plasma drug concentrations, it is therefore necessary to monitor unbound as well as total concentrations because the effects on these differ greatly.

Aged↗
PubMed1988

Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction.

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu(b)) on steady state total (Cb) and unbound (Cu(b)) blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL(int)). For a substance of very low CL(int), if fu(b) changes, Cb will change and Cub will remain constant, whereas if CL(int) is very high, Cub will change and Cb will remain constant. The present study defines the effects of a change in fu(b) on Cb and Cub over the whole CL(int) range. Computer simulations were undertaken which predicted that, for a given change in fu(b), absolute and relative changes in Cb would decrease nonlinearly with increasing CL(int), while the relative change in Cub would increase with CL(int). The absolute change in Cub would be independent of CL(int). Significant changes in Cb and Cub would be observed at intermediate values of CL(int) not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu(b) of sodium taurocholate a substance with intermediate CL(int) (such that at fu(b) = 0.27, hepatic extraction ratio = 0.71) induced by concurrent administration of sodium oleate. Sodium 24-14 C-taurocholate (specific activity 52 microCi/mmol) was infused into the reservoir in a recycling system at 30 mumol/hr for 105 min (n = 6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu(b) fell promptly by 55% (0.27-0.12). There was a relative increase of taurocholate Cb of 22.7% and a relative decrease in Cub of 45.4%, in accordance with the simulations (p less than 0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.

Animals↗
PubMed1988

Effect of plasma protein binding on elimination of taurocholate by isolated perfused rat liver: comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models.

In the past, various models have been developed to allow better characterization of the hepatic elimination of substrates from plasma. In this study we investigated the applicability of the venous equilibrium, undistributed sinusoidal, several distributed sinusoidal, and dispersion models to the steady state elimination of sodium taurocholate by the isolated perfused rat liver. Rat livers were perfused with 24-14C-taurocholate (sodium salt) at a concentration of 25 microM (specific activity 500 microCi/mmole) in a single-pass design (n = 7) or at a rate of 0.5 mumol/min (specific activity 40 microCi/mmole) into the portal vein in a recirculating design (n = 5). In single-pass experiments, the changes in hepatic venous outflow concentration (C0) with changes in unbound fraction of taurocholate (fu) from 0.09 to 1.0 were fitted better by the venous equilibrium model, by the dispersion model, and by a distributed model in which heterogeneity in both hepatic blood flow (Q) and intrinsic clearance (CLint) was defined by separate density functions. The very large value of dispersion number (DN greater than 10(7] yielded by the dispersion model is consistent with a high degree of axial mixing of blood within sinusoids. The large coefficients of variation (0.7-232) for the density functions describing the transverse heterogeneity of Q and CLint obtained with the Q/CLint-distributed model were consistent with a large degree of heterogeneity in Q and CLint within the liver. In recirculation experiments, the steady state unbound concentration of taurocholate in the reservoir (Cuss) was independent of fu (range 0.05-0.9). This finding was not predicted by the undistributed sinusoidal model, but was in keeping with the venous equilibrium model, with the dispersion model, and with the Q/CLint-distributed model. Therefore, there is no need to invoke cell surface-mediated dissociation of albumin-ligand complexes in hepatic taurocholate uptake. As the dispersion and Q/CLint-distributed models are conceptually plausible and operationally accurate, it may be time to relinquish the venous equilibrium model, which, though operationally accurate, is conceptually flawed.

Animals↗
PubMed1988

Lack of linear correlation between hepatic ligand uptake rate and unbound ligand concentration does not necessarily imply receptor-mediated uptake.

Previous studies of the hepatic uptake of several albumin-bound ligands, using constant and variable albumin concentrations, were interpreted as being inconsistent with the traditional mechanism of uptake, defined as an uptake rate directly proportional to unbound ligand concentration, and led to the formulation of the albumin receptor theory of hepatic uptake. Because other experimental designs have failed to confirm the albumin receptor theory, we reexamined, using the isolated perfused rat liver preparation, the traditional uptake mechanism under the conditions used in the original studies, of constant and variable albumin concentration. Livers (n = 6) were perfused in randomized sequence with 10 different solutions containing 24-14C-taurocholate in a single-pass design. Five solutions contained fixed albumin (0.1 mM) and variable taurocholate (3-48 microM) concentrations, and five maintained the taurocholate-albumin ratio fixed at 0.06; absolute concentrations of taurocholate varied from 3-48 microM, and of albumin from 0.05-0.08 mM. At constant albumin concentration in hepatic inflow, elimination rate of taurocholate was linearly related to both total (Cin) and unbound (Cin,u) taurocholate concentration in hepatic inflow, indicating first-order elimination kinetics. When taurocholate and albumin were increased in hepatic inflow in a fixed molar ratio, taurocholate uptake rate was not linearly related to Cin,u but was still consistent with the traditional uptake mechanism. Moreover, the apparent saturation of taurocholate uptake by added albumin was consistent with the reduction in unbound fraction (fu) in accordance with the traditional uptake mechanism. This study shows that although the traditional uptake mechanism dictates that ligand uptake rate is linearly related to unbound ligand concentration within the liver, uptake rate need not necessarily be linearly related to Cin,u. Therefore, experiments in which lack of a linear relationship between uptake rate and Cin,u is found do not necessarily imply receptor-mediated uptake.

Animals↗
PubMed1988

The effects of cardiopulmonary bypass on plasma concentrations and protein binding of methohexital and thiopental.

The effects of cardiopulmonary bypass (CPB) on plasma concentrations and protein binding of methohexital and thiopental were studied during continuous infusions in two groups of ten cardiac surgical patients. Patients were administered an infusion regimen designed to produce a stable total plasma concentration at 5 mg/L for methohexital and 10 mg/L for thiopental. Prior to the commencement of CPB the mean (+/-SD) total plasma methohexital concentration was 5.00 +/- 0.69 mg/L. This fell to 3.12 +/- 0.89 mg/L at two minutes after commencement of CPB, and rose to 4.67 +/- 1.11 mg/L by 75 minutes after commencement of CPB. The unbound fraction rose from 27.1 +/- 5.1% to 42.8 +/- 9.2% at five minutes after the start of CPB, and gradually decreased to 32.1 +/- 4.9% by 75 minutes. The unbound concentration (1.37 +/- 0.32 mg/L) was unaffected by the onset of CPB, being 1.51 +/- 0.49 mg/L at 75 minutes after the start of CPB. Thiopental followed a similar pattern to methohexital, with the total plasma thiopental concentration falling from 9.22 +/- 0.73 mg/L to 4.90 +/- 0.83 mg/L at two minutes after commencement of CPB, and rising again to 7.13 +/- 1.03 mg/L 75 minutes later. During the same period the unbound fraction of thiopental rose from 16.1 +/- 2.5% to 30.3 +/- 7.3% five minutes after the start of CPB, and fell gradually to 22.8 +/- 5.8% after 75 minutes. The unbound concentration (1.51 +/- 0.21 mg/L) was again unchanged by the onset of CPB, being 1.71 +/- 0.29 mg/L at 75 minutes. Plasma protein binding of both drugs correlated strongly with plasma albumin concentration, which decreased by 40% during CPB. It is concluded that hemodilution caused the reduction in total drug concentration and protein binding at the onset of CPB, but that the decrease in protein binding counteracted the dilution of unbound drug, resulting in a stable unbound concentration throughout CPB, and that this effect may be common for barbiturates.

Analysis of Variance↗
PubMed1988

Extended blood collection period required to define distribution and elimination kinetics of propofol.

The pharmacokinetics of propofol were investigated following bolus intravenous administration of 2-3 mg kg-1 of drug to eight surgical patients. Apparent elimination half-life, volume of distribution and systemic blood clearance of propofol correlated strongly with the sampling period, which ranged from 8 to 52 h, depending on the time taken for the propofol concentration to reach the detection limit of the assay. In the three patients in whom the sampling period exceeded 42 h, apparent elimination half-life (55.6 h) and apparent volume of distribution (1370 l) greatly exceeded previously published estimates and systemic blood clearance (1020 ml min-1) was much less than previous estimates. This suggests that previous estimates were biased by the relatively short duration of blood collection in those studies (8 to 12 h).

Adult↗
PubMed1988

Effects of gestational age on the disposition of propranolol in pregnant sheep.

Maternal and fetal disposition of the beta adrenoceptor blocking drug, propranolol was examined in the pregnant sheep from day 95 to day 140 (term, 145 days) of gestation. Propranolol was administered to the mother (bolus dose, 1.5 mg/kg followed by an infusion of 1.2 mg/kg/hr over 3 hr) to achieve an average steady-state maternal total drug concentration of 600 ng/ml. Total steady-state maternal plasma propranolol concentration was 666 +/- 266 ng/ml, reflecting a 4-fold variation in maternal drug clearance and a 14-fold variation in binding. Neither maternal clearance nor binding showed a significant change with gestational age. Total plasma drug concentrations in the fetus increased significantly with gestational age (r = 0.58, P less than .05), due to a concomitant increase in binding (r = 0.66, P less than .01). Fetal steady-state unbound drug concentrations were 50% of those seen in the mother, indicating that the fetus is capable of irreversible elimination of the drug. This ratio did not change with gestational age, suggesting that the capacity of the fetus to eliminate propranolol does not increase detectably in the latter part of pregnancy. The significant correlation between maternal and fetal unbound drug concentrations indicates that a major determinant of fetal exposure to propranolol is the clearance of the drug by the mother.

Animals↗
PubMed1988

Mechanism of triamterene transfer across the human placenta.

The diuretic, triamterene, had been regarded to be a drug which was actively transported by the placenta from fetus to mother. In the present study, the transfer of triamterene across the isolated perfused human placenta was examined. Placentas obtained at cesarean section were perfused for up to 2 hr from both maternal and fetal sides in either single-pass or recycling constant flow systems. In single-pass experiments, the placental clearance of triamterene (400 ng/ml) from mother to fetus or from fetus to mother was examined (n = 8). Antipyrine (20 micrograms/ml) and l-leucine (0.25 mM) were used as reference compounds. The transplacental clearance index (i.e., clearance relative to antipyrine clearance) of triamterene from mother to fetus (0.85 +/- 0.10) was similar to the clearance index from fetus to mother (0.74 +/- 0.08, P greater than .10), indicating rapid transfer across the placenta, but no active fetal to maternal transport. In contrast, the l-leucine clearance index from mother to fetus (0.62 +/- 0.05) was substantially greater than that from fetus to mother (0.27 +/- 0.03, P less than .01), consistent with active maternal to fetal transport. In recycling experiments (n = 5), with test compounds added in equal concentration to both maternal and fetal circuits, the equilibrium fetal/maternal perfusate concentration ratios were 1.41 +/- 0.02 for l-leucine and 0.98 +/- 0.01 for antipyrine. The slightly lower value for triamterene (0.92 +/- 0.02) probably reflected minor differences in protein binding between maternal and fetal circuits.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗
PubMed1987

Pharmacokinetics and metabolism of salbutamol in premature labour.

1 The pharmacokinetics of salbutamol and its sulphate conjugate were examined during intravenous and steady-state oral administration in nine patients receiving the drug for the prevention or treatment of premature labour. 2 Uterine contractions were inhibited by plasma salbutamol concentrations in the range 8-33 ng ml-1 in six of the seven patients who were receiving intravenous drug. 3 By comparison with our previous study in a control group of healthy males and nonpregnant females, the total clearance of salbutamol in premature labour (501; s.d. 185 ml min-1) was similar to that in the control group (480; s.d. 123 ml min-1). Renal salbutamol clearance (208; s.d. 51 ml min-1), however, was significantly less than that in the control group (283; s.d. 51 ml min-1). 4 The systemic availability (n = 3), urinary recovery of unchanged oral salbutamol and area under the plasma curve during the oral dosage interval (n = 5) were all only slightly lower (10-20%) than control values, suggesting slightly lower oral absorption. 5 Formation and elimination of the sulphate conjugate were similar to those observed in control subjects suggesting that first-pass sulphation in the gut wall is unchanged in pregnancy. Overall there were only minor differences in salbutamol pharmacokinetics between control subjects and patients in premature labour.

Administration, Oral↗
PubMed1987

Plasma bupivacaine concentrations during postoperative continuous epidural analgesia.

Postoperative analgesia and plasma concentrations of bupivacaine were evaluated in six patients receiving intermittent epidural bupivacaine for a period of 72 hours following large bowel surgery. Repeated doses were administered every hour by a new automatic, specially designed pump. Venous plasma bupivacaine concentrations showed accumulation for up to 48-60 hours during administration and were mostly less than 2 micrograms/ml except in an elderly, frail patient in whom a peak of 3.9 micrograms/ml was observed. This convenient, low-dose, pulsed technique provided excellent analgesia although special care may be necessary in the elderly and frail patient if potentially toxic levels are to be avoided.

Adult↗
PubMed1987

Hypoxia impairs conjugation and elimination of harmol in the isolated perfused rat liver.

Although studies in isolated hepatocytes have demonstrated that hypoxia adversely affects drug conjugation, the impact of hypoxia on drug elimination by conjugation in the intact liver has not been defined. This study in the isolated perfused rat liver examines the effect of acute hypoxia on the hepatic elimination of harmol, a phenolic compound eliminated by conjugation without first undergoing oxidative metabolism. In the preparation used in these experiments, harmol glucuronide is the major metabolite (greater than 80%), with the remainder being sulfate. The hypoxic insult consisted of an 80% reduction of hepatic oxygen delivery for 1 hr. During normal oxygenation, a 20-mumol dose was rapidly eliminated (T1/2 = 4.3 +/- 0.8 min; mean +/- S.D., n = 5). A second dose given after 30 min of hypoxia was eliminated much more slowly (T1/2 = 21 +/- 7.9 min, P less than .01). Upon reoxygenation, T1/2 recovered to 4.2 +/- 0.5 min. Similar effects were observed in steady-state experiments, in which perfusate levels rose from 15.7 +/- 1.3 microM to 31.0 +/- 1.6 microM (P less than .005) during hypoxia, indicating a fall in harmol clearance of at least 50%. In each group of experiments, there was a significant reduction in both the formation and elimination of harmol conjugates during hypoxia. Upon reoxygenation, harmol conjugation recovered, but conjugate elimination remained significantly impaired. The authors conclude that acute hypoxia slows the hepatic elimination of harmol by reducing drug conjugation, an effect that is promptly reversed by reoxygenation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1987

Low clearance of cimetidine across the human placenta.

The transfer of cimetidine across the isolated perfused human placenta was examined. Placentas obtained at cesarean section were perfused for 2 hr from both maternal and fetal sides in constant flow recycling systems. Cimetidine was administered as a bolus dose to either the maternal circuit alone (n = 4) or to both maternal and fetal circuits simultaneously (n = 3), to achieve initial concentrations of 4 micrograms/ml. Antipyrine (20 micrograms/ml) and l-leucine (0.25 mM) were administered in like fashion as reference compounds. Two hours after maternal dosage there was equilibration of antipyrine across the placenta, but equilibration of cimetidine was incomplete (fetal/maternal ratio = 0.46 +/- 0.07). The fetal/maternal ratio of l-leucine was greater than unity; consistent with active maternal to fetal transport. Maternal to fetal cimetidine transplacental clearance (0.50 +/- 0.05 ml/min) was 23% of antipyrine clearance. After simultaneous dosage to both maternal and fetal circuits, the l-leucine fetal/maternal ratio was 1.37 +/- 0.08 at 2 hr and maternal and fetal levels of cimetidine and antipyrine were at equilibrium for the duration of the experiment (fetal/maternal ratio of cimetidine = 1.01 +/- 0.02). This study shows that cimetidine is transferred across the human placenta by passive diffusion. In contrast to the rapid placental transfer demonstrated by the majority of drugs studied previously, the placental transfer of cimetidine is slow. We conclude that the human placenta may therefore provide significant protection of the fetus from a single maternally administered dose of cimetidine.

Antipyrine↗
PubMed1986

Relationships among duration of infusion, dose, dosing interval, and steady-state plasma concentrations during intermittent intravenous infusions: studies with metronidazole.

Relationships among duration of infusion (T), dose, dosing interval (tau), maximum and minimum plasma drug concentrations at steady state (Cmax,ss and Cmin,ss, respectively), and the duration of effective plasma concentrations (tD) during multidose intermittent infusion regimens were studied by computer simulation using metronidazole as a model drug. Pharmacokinetic parameter values for metronidazole were obtained from the literature and the minimum effective plasma concentration (MEC) was taken as 6.0 micrograms/ml. Increasing the infusion period of the dose reduces Cmax,ss, but increases Cmin,ss. If intermittent bolus injection of a given dose of drug results in effective plasma concentrations for the entire dosage interval (i.e., Cmin,ss,bolus greater than MEC), then infusion of that dose over any period (T less than or equal to tau) will also result in effective concentrations for the entire dosage interval. However, if the dosage is such that Cmin,ss,bolus less than MEC, the relationships among duration of infusion, dose, dosage interval, and duration of effective plasma concentrations are complex. Therefore a nomogram was developed to allow selection of dose, dosing interval, and infusion period such that Cmax,ss and Cmin,ss could be maintained within a desired range.

Humans↗
PubMed1986

Influence of intravenous infusion duration on the tissue drug concentration profile.

The influence of intravenous infusion duration of a single dose of drug on the time course of drug concentration in the peripheral compartment of the classical two-compartment pharmacokinetic model was studied by computer simulation. The aim was to illustrate the general relationships among infusion duration T, dose, minimum effective concentration MEC at the effector (tissue) site, maximum tissue drug concentration C2,max, and the duration of effective tissue concentrations tD,tiss for those drugs where there is an equilibration delay between concentration at the effector site and plasma. Simulations of C2,max vs. T for meperidine, sulfamethoxazole, ampicillin, and metronidazole showed that, although maximum plasma concentration may decrease markedly with increasing T, C2,max decreased only slightly with increasing T. Simulations of the influence of T on the duration of effective plasma concentrations tD and tD,tiss of metronidazole showed that for a given T, tD,tiss may be greater than or less than tD, depending on the dose, and that it is possible to obtain effective concentrations in the tissue compartment even though the infusion duration is too long to achieve effective concentrations in plasma. It was found that, depending on the dose, it was possible to cause an increase in tD,tiss compared with bolus administration by increasing the infusion duration of the dose. It was also found that increasing T could cause opposite changes in tD and tD,tiss (compared with bolus administration, respectively), e.g., an increase in tD and a decrease in tD,tiss or vice versa, depending on the dose. It should thus be possible to make precise predictions of the influence of T on drug concentration at the effector site for individual drugs by incorporating effect compartment modeling into the analysis.

Computer Simulation↗
PubMed1986

Thiopentone levels during cardiopulmonary bypass. Changes in plasma protein binding during continuous infusion.

Plasma total and unbound concentrations of thiopentone were investigated during exponentially decreasing infusions in seven patients undergoing cardiopulmonary bypass. Total plasma thiopentone concentrations reached a plateau (10.2, SD 2.1 micrograms/ml) soon after the initial bolus dose and commencement of the infusion. Concentrations were maintained until the onset of cardiopulmonary bypass, whereupon total plasma thiopentone concentration fell abruptly to 50.0 (SD 5.8) percent of the prebypass level. The unbound fraction of thiopentone increased from 16.6 (SD 1.9) percent before bypass to a maximum of 29.3 (SD 5.6) percent during bypass (p less than 0.01), decreased to 22.9 (SD 3.3) percent at the end of bypass (p less than 0.01), but was still elevated 5-7 hours later (20.5, SD 2.5 percent). The result of the changes in binding was a smaller decline in unbound thiopentone concentration at the onset of bypass to 76.4 (SD 15.7) percent of the prebypass level. Also, unbound levels returned to the prebypass level by the end of bypass, whereas total levels remained low.

Adult↗
PubMed1986

Pharmacokinetics of intravenous and oral salbutamol and its sulphate conjugate.

The pharmacokinetics of salbutamol and its sulphate conjugate metabolite were investigated after intravenous and steady-state oral administration of salbutamol to 10 healthy volunteers. With intravenous administration, total plasma clearance was 480 +/- 123 ml min-1, elimination half-life was 3.86 +/- 0.83 h and apparent volume of distribution was 156 +/- 381. Urinary excretion of unchanged drug and sulphate conjugate were 64.2 +/- 7.1% and 12.0 +/- 3.1% of the dose, respectively. With oral administration, systemic availability was 0.50 +/- 0.04, and urinary excretion of unchanged drug and sulphate conjugate were 31.8 +/- 1.9% and 48.2 +/- 7.3% of the dose, respectively. The drug eliminated on the first-pass could be accounted for entirely as sulphate conjugate formed, presumably, in the intestinal wall. Renal clearance of salbutamol was 291 +/- 70 ml min-1 after intravenous and 272 +/- 38 ml min-1 after oral administration, while the renal clearance of the sulphate conjugate was 98.5 +/- 23.5 ml min-1 after oral administration. Heart rate increased with increasing plasma salbutamol concentration, although a lag was evident. The effect on heart rate was lower after 24 h continuous oral salbutamol administration.

Administration, Oral↗