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D J Morgan

Publications and source records attributed to D J Morgan.

205 records · Page 12Linked to original sources
PubMedDate not supplied

The developing liver: the steady-state disposition of propranolol in pregnant sheep.

The steady-state disposition of the beta-adrenoreceptor blocking drug, propranolol, and its metabolite, 4-hydroxypropranolol, was studied in the anesthetized pregnant sheep near term. Following infusion of propranolol to the mother, steady-state plasma concentrations were obtained at three dosage levels in each of the eight animals studied. Blood samples were obtained from : (i) maternal facial artery and hepatic vein; (ii) umbilical vein, and (iii) fetal carotid artery, portal vein, and right hepatic vein. Although total propranolol concentrations in maternal plasma were different from those in umbilical venous plasma, the concentrations of unbound drug were similar, suggesting that unbound drug had equilibrated across the placenta. Approximately 10% of propranolol was unbound in maternal plasma, compared with 30% in fetal plasma. Hepatic extraction of propranolol by the maternal liver was high, so that only 3 to 4% of the drug presented to the liver escaped uptake. In contrast, fetal hepatic extraction was low. Negligible amounts were removed from portal vein blood (right lobe), although one third was extracted from umbilical vein blood (left lobe). Mean peripheral arterial concentrations of 4-hydroxypropranolol were 2- to 3-fold higher in the fetus than in the mother. We conclude that the fetus is exposed to significant concentrations of propranolol and that the fetal hepatic extraction of this drug is considerably less efficient than in the adult. In contrast to the adult liver, the fetal liver does not appear to act as a single homogeneous organ, but rather as two distinct subunits.

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Differential effects of hypoxia on the disposition of propranolol and sodium taurocholate by the isolated perfused rat liver.

Although the adverse effect of hypoxia on drug metabolism is well documented in subcellular systems, its effect on drug clearance by the intact liver has not been defined. This study was undertaken in the isolated perfused rat liver to examine the effects of acute hypoxia on the hepatic elimination of two highly cleared substances--propranolol and sodium taurocholate. Hypoxia was established by equilibrating the perfusate with 100% nitrogen rather than 100% oxygen. This led to a fall in portal vein pO2 from 300 to 30 mm Hg, and a 10-fold rise in hepatic venous lactate:pyruvate ratio, indicating a profound alteration in hepatic cellular redox state. In bolus dose studies, propranolol uptake was unimpaired by hypoxia, with a monoexponential decline in perfusate concentrations from 2,000 to 30 ng per ml, (t1/2 uptake = 2.5 min). After 20 min of hypoxia, perfusate propranolol concentrations rose from 30 to 80 ng per ml, indicating release of propranolol from liver back into the perfusate. Reoxygenation of perfusate restored hepatic extraction of propranolol to normal (t1/2 uptake = 2.37 +/- 0.19 min vs. 2.55 +/- 0.60 min p greater than 0.1) such that perfusate concentrations were undetectable by 30 min. In steady-state studies, perfusate propranolol concentrations rose from 1.55 +/- 0.50 to 4.08 +/- 1.47 micrograms per ml (p less than 0.005), after 1 hr of hypoxia indicating a change in propranolol clearance from 15 ml per min to less than 6 ml per min. Reoxygenation resulted in a fall in perfusate propranolol concentrations towards control values (2.78 +/- 1.13 vs. 1.80 +/- 0.41 micrograms per ml, p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

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A carrier-protein receptor is not a prerequisite for avid hepatic elimination of highly bound compounds: a study of propranolol elimination by the isolated perfused rat liver.

The highly efficient hepatic extraction of propranolol by the isolated perfused rat liver does not diminish when albumin binding is increased from 30 to 75%. One possible explanation of this insensitivity of propranolol uptake to changes in albumin binding is the mediation of uptake of bound ligand by an albumin receptor on the hepatocyte as postulated for oleate, taurocholic acid and rose bengal. To test this hypothesis, the hepatic extraction of propranolol was studied in the isolated perfused rat liver using alpha 1-acid glycoprotein, which lacks a hepatocyte receptor, as the carrier protein in the perfusate rather than albumin. Livers were perfused with a medium containing propranolol (4 microM) and varying concentrations of alpha 1-acid glycoprotein (0 to 25 microM). Hepatic extraction of propranolol was very high (0.990 +/- 0.006; mean +/- S.D.) and did not alter significantly despite an increase in bound fraction from 0.2 to 0.8, thus closely paralleling the findings when albumin is the carrier protein. This result indicates that bound propranolol is efficiently cleared by the liver, presumably by a "free intermediate" mechanism, in the absence of a specific carrier-protein receptor on the hepatocyte. This study does not, therefore, support the albumin receptor hypothesis.

Albumins↗
PubMedDate not supplied

Transfer of acipimox across the isolated perfused human placenta.

The placental transfer of the new lipid-lowering agent, acipimox was investigated in the isolated perfused human placenta. Placentas obtained at caesarean section were perfused for 120 min, with both maternal and fetal circuits in closed recycling mode. Acipimox was added to either the maternal circuit alone (five experiments) or to both maternal and fetal circuits simultaneously (five experiments) to achieve initial concentrations of 5 micrograms/ml. Antipyrine (20 micrograms/ml) and l-(14C)-leucine (250 microM) were added in like fashion as reference compounds. Two hours after addition to the maternal circuit alone antipyrine was close to equilibrium across the placenta, but equilibration of acipimox was incomplete (fetal/maternal ratio = 0.58 +/- 0.11). Maternal to fetal placental clearance of acipimox (0.80 +/- 0.18 ml/min) was 25 per cent of antipyrine clearance. After simultaneous administration to both maternal and fetal circuits the l-(14C)-leucine fetal/maternal ratio was 1.44 +/- 0.13 at 120 min, whereas maternal and fetal concentrations of acipimox and antipyrine were at equilibrium for the duration of the experiment (fetal/maternal ratio of acipimox at 120 min = 1.10 +/- 0.06). This study shows that acipimox is transferred across the human placenta by diffusion at a slow rate. The low permeability of the placenta may afford some protection to the fetus from acipimox administered to the mother in vivo.

Antipyrine↗
PubMedDate not supplied

Accuracy of volume measurement using helical CT.

PURPOSE: Our goal was to determine the accuracy of volume estimation using helical CT. METHOD: Helical CT scans were conducted with regularly and irregularly shaped polyvinylchloride bags containing saline of varying volumes immersed in peanut oil during various rates of movement of 0, 10, 15, and 20 cycles/min, using a motorized platform, designed to simulate respiratory motion. Ten cancer patients were scanned with CT to determine optimum upper and lower Hounsfield unit thresholds. The volumes of two human livers and kidneys were also measured in vitro under the same conditions. RESULTS: For all conditions, the accuracy and bias of volume estimation for saline bags ranged from 95.0 to 99.2 and -3.46 to 4.04%, respectively, and the accuracy and bias for the estimation of liver and kidney volumes were 95.6 and 3.12%, respectively. CONCLUSION: This study shows that helical CT is a highly accurate technique for estimating volume, even in the presence of simulated respiratory motion.

Humans↗
PubMedDate not supplied

Permeability of myocardial capillaries to hydrophilic drugs: the paracellular pathway.

1. As the majority of drug molecules are relatively small and lipophilic, capillary uptake in those regions with a continuous endothelium, such as the heart, has generally been regarded as taking place by flow-limited transcellular capillary transport. Little attention has been paid to myocardial paracellular capillary transport of hydrophilic drugs, despite efficient transport of hydrophilic solutes, such as sucrose, inulin and EDTA, by this route. 2. The paracellular pathway is formed by the cleft between adjacent endothelial cells and its permeability properties are determined by the tight junction, a region of restricted diameter within the cleft. Paracellular capillary permeability is modulated by circulating macromolecules, such as albumin, by an unknown mechanism thought to involve the intra-endothelial cell Ca2+ concentration. 3. Studies in perfused rat heart have shown that capillary permeability of quinidine does not vary when perfusate pH is varied from 7.0-8.0, suggesting that capillary transport involves the ionized as well as unionized moiety. Addition of albumin to the perfusion medium reduced quinidine capillary permeability, which is consistent with paracellular transport of quinidine ions. 4. Paracellular transport increases in capillary inflammation. Therefore, if there is significant paracellular transport of hydrophilic drugs, an increase in uptake of such drugs in areas of inflamed myocardium associated with acute myocardial infarction would be expected to result.

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