Biomedical subjects

D J Morgan

Publications and source records attributed to D J Morgan.

At least 91 records · Page 5Linked to original sources

PubMed1994

Hepatic uptake and excretion of [14C]sodium taurocholate by the isolated perfused fetal sheep liver.

We have developed an in situ isolated perfused fetal sheep liver preparation to study fetal hepatic function free from the confounding influences of the mother and other fetal organs, and we have used the preparation to study the fetal hepatic clearance and biliary excretion of sodium taurocholate (TC). The viability and stability of this model were established by monitoring perfusion pressure, oxygen consumption, perfusate enzymes and electrolytes, the perfusate concentration ratio of lactate to pyruvate, bile flow, and liver histology. Perfusate delivery was 300 mL/min with a mean value of 3.94 mL/min/g liver (range: 2.46-6.72 mL/min/g liver). Gadolinium radiolabeled 15 microns microspheres were used to quantify the ductus venosus shunt through the liver and to determine relative flow rates between right and left hepatic lobes. TC was added to the reservoir either as a [14C]TC tracer bolus dose (2 microCi, N = 5) followed by a constant infusion of unlabeled TC, or as an initial bolus of [14]TC (54 mumol) followed by a [14C]TC constant infusion (30 mumol/hr, specific activity 30 microCi/mmol; N = 3). Perfusate samples were taken from the reservoir every 15 min and bile was collected in 30 min aliquots. Perfusion pressure (7.9 +/ 0.30 mmHg), perfusate potassium and oxygen consumption (0.9 +/- 0.07 mumol/min/g liver) were constant throughout, and the perfusate lactate/pyruvate concentration ratio was low (< 20). Liver histology showed no hypoxic changes. Bile flow fell slightly over the 150 min experiment time from 0.6 to 0.5 muL/min/g liver. These data indicate preparation viability and stability. The extent of the ductus venosus shunt was 16-66% (mean 35 +/- 6%) of umbilical vein flow, which correlated inversely with fetal gestational age (r = 0.94, P < 0.001). Relative flow to right and left lobes of liver was 1:1.4. In bolus dose experiments, TC t1/2 was 81.6 +/- 26 min, clearance (Cl) was 35.0 +/- 22.6 mL/min, shunt corrected extraction (E*) was 0.29 +/- 0.17 and biliary clearance (ClB) was 35.5 +/- 19.5 mL/min. In constant infusion experiments the corresponding results were Cl: 34.7 +/- 18.2, E*: 0.23 +/- 0.16, and ClB 32.7 +/- 17.7. The cumulative biliary excretion of [14C]TC in bolus dose experiments was 86.5 +/- 8.7% of the dose, and in constant infusion experiments, concentration of TC in bile was on average over 800 times that in plasma.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Intracellular binding is an important determinant of the avid hepatic uptake of the high clearance drug omeprazole.

The contribution of intracellular storage to hepatic uptake of the high clearance drug, omeprazole, was examined in the recirculating isolated perfused rat liver preparation. Following injection of [3H]omeprazole (7.5 microCi, 5 mg) into the portal vein over 1 min, livers were perfused for 5 min (N = 3) or 30 min (N = 3) and then homogenized at 4 degrees and fractionated by differential centrifugation. Radiolabelled omeprazole and metabolites were determined by scintillation counting of fractions of eluant from HPLC. Seventy per cent of drug had been taken up by the liver at 5 min and 85% at 30 min, with unchanged drug representing 43 and 7.4%, respectively, of drug taken up. At both times, 70-75% of intracellular unchanged drug and the major metabolites were located in the cytosol, and the cytosol:perfusate concentration ratio was approximately 10:1. Mitochondrial, lysosomal and microsomal fractions contained relatively little drug. Extensive cytosolic binding of omeprazole therefore contributes substantially to the initial avid hepatic first-pass uptake of this drug.

Animals↗

PubMed1994

Abnormal bacterial colonisation of the genital tract and subsequent preterm delivery and late miscarriage.

OBJECTIVE: To find out whether women with bacterial vaginosis detected early in pregnancy are at increased risk of preterm delivery. DESIGN: Prospective description cohort study. SETTING: Antenatal clinic in a district general hospital. SUBJECTS: 783 women examined during their first antenatal clinic visit and screened for recognised risk factors for preterm delivery and the presence of bacterial vaginosis or intermediate abnormal flora detected by examination of a vaginal smear stained by Gram's method. MAIN OUTCOME MEASURES: Gestational age at delivery classified as late miscarriage (16-24 weeks' gestation), preterm delivery (24-37 weeks' gestation), term delivery (> or = 37 weeks' gestation). RESULTS: Multiple logistic analysis showed that there was an increased incidence of preterm delivery in women with a previous preterm delivery (9/24; odds ratio 25; 95% confidence interval 9 to 70; P < 0.001) and bacterial vaginosis (9/115; 2.8; 1.1 to 7.4; P = 0.04). A further logistic analysis of data from women recruited before 16 weeks' gestation showed that preterm deliveries or late miscarriages occurred more often in women with bacterial vaginosis (12/77; 5.5; 2.3 to 13.3; P < 0.001). CONCLUSIONS: Late miscarriage and preterm delivery are associated with the presence of bacterial vaginosis in early pregnancy. This is independent of recognised risk factors such as previous preterm delivery.

Abortion, Spontaneous↗

PubMed1994

Influence of perfusion flow rate on uptake and pharmacodynamics of quinidine in isolated perfused rat heart.

With the single-pass isolated perfused rat heart preparation, we examined the effect of perfusate flow rate on the time course of quinidine output concentration (Cout) and the change in the QT interval (delta QT) on the electrocardiogram. Four hearts were perfused at 5.6 mL/min with quinidine (20 microM) for 25-45 min. This was followed by a 50-min washout period with drug-free perfusate. This procedure was repeated four times in each heart. Using a one-compartment model, the rate constants calculated from the time course of Cout (k) and delta QT (Ke) were similar (p > 0.05) and did not vary among the five phases. A zero-time intercept for Cout indicated shunting of perfusate (1.2-13.6%), from which the coronary output concentration (Ccor) and coronary flow rate were calculated. These experiments were repeated in another six hearts, except flow rates of 2, 4, 6, 8, and 2 mL/min were used in each phase. Equilibration of Cout and delta QT was faster with increasing flow rate, and ke and k were similar at each flow rate (p > 0.05). A modified Kety-Renkin-Crone equation was fitted to values for k and coronary flow rate. The mean permeability surface product estimate was 15.3 +/- 3.0 mL/min/g heart, which in comparison with the highest flow rate used (9 mL/min/g heart) suggests that quinidine has intermediate permeability. The excellent fit obtained indicates that a more complex model, incorporating heterogeneous flows or opening of capillaries at higher flows, was not necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Product inhibition and dose-dependent bioavailability of propranolol in the isolated perfused rat liver preparation.

We investigated in the isolated perfused rat liver (IPRL) whether product inhibition of metabolism contributes to the dose-dependent bioavailability of propranolol, a drug with a high, but saturable, hepatic first-pass effect. (+/-)-Propranolol was infused in the IPRL, using a recirculating design, for three 36-min periods (n = 9). Mean steady-state reservoir, i.e. hepatic inflow concentrations (Cin), were 4.97, 10.4, and 20.4 microM, respectively. Mean reservoir concentrations of the metabolites 4'-hydroxypropranolol, 5'-hydroxypropranolol, N-desisopropylpropranolol, and naphthoxylactic acid (NLA), a major side-chain-oxidation metabolite, increased disproportionately with propranolol dose, but their production rate did not reach steady state. In separate experiments (n = 4), perfusate containing 7.1, 12.8, and 21.6 microM (+/-)-propranolol, corresponding to administration rates of 114, 205, and 346 nmol/min, respectively, was passed through the liver for 30 min each using a single-pass design. The bioavailability (hepatic outflow concentration/Cin) of propranolol increased with Cin from 0.012 to 0.150 to 0.288 in the recirculating IPRL. In the single-pass IPRL the increase (0.0077 in 0.0669 to 0.136) was significantly less (P < 0.001). The greater bioavailability of propranolol in recirculating experiments was attributed to product inhibition since metabolites do not accumulate with the single-pass design. NLA did not appear to be the inhibiting metabolite because in further single-pass experiments with propranolol Cin of 21.6 microM the presence of NLA (21.6 microM) in perfusate had no effect on propranolol bioavailability (n = 7) compared with control experiments (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Hepatic Kupffer cell function: the efficiency of uptake and intracellular degradation of 14C-labelled mitochondria is reduced in aged rats.

Uptake from the circulation and subsequent intracellular degradation of foreign and potentially harmful substances are key functions of hepatic Kupffer cells. While ageing is generally associated with decreased clearance by the reticulo-endothelial system, the effect of ageing on specific Kupffer cell functions is poorly understood. This study measured the ability of Kupffer cells of isolated perfused rat livers from young and old rats to both phagocytose and subsequently degrade exogenous radiolabelled mitochondria. Using electron microscopy and stereological techniques it was determined that there was no change in the volume density of Kupffer cells between 2 and 24 months, implying that the size of the Kupffer cell population increased (along with the total liver size) with age. However, despite this increase size there was no parallel increase in the capacity of the liver to take up or degrade radiolabelled mitochondria, implying that, in aged rats, Kupffer cell uptake and intracellular degradation was less efficient.

Aging↗

PubMed1994

Effect of perfusate pH on reduction of quinidine capillary permeability by albumin in isolated perfused rat heart.

It has been suggested that albumin reduces quinidine capillary permeability (PS) in the single-pass perfused heart preparation by reducing paracellular transport of quinidine ions. Using this preparation, we examined the effect of albumin (0.1 per cent) on quinidine PS at perfusate pH's of 7.1 and 7.9 during uptake of quinidine (19 microM) and also during washout of the drug using a randomized design. Quinidine PS was approximately 16 ml/min/g heart at pH 7.9 and was not altered by the presence of albumin in perfusate. At pH 7.1, in the absence of albumin, quinidine PS was also 16 ml/min/g, but in the presence of albumin (0.1 per cent) PS was reduced significantly to approximately 5 ml/min/g (P < 0.001). In the absence of albumin PS was the same at pH 7.1 and 7.9 in spite of a greater degree of ionisation of quinidine at pH 7.1. This suggests that there is significant uptake of ionised quinidine at pH 7.1. The greater effect of albumin on PS at pH 7.1 supports the hypothesis that albumin reduces paracellular transport of quinidine ions.

Animals↗

PubMed1994

Lean body mass, body surface area and epirubicin kinetics.

For a number of cytotoxics, a relationship between efficacy and plasma concentrations has recently been demonstrated. Lean body mass has been demonstrated to be a useful parameter for predicting drug clearance for a number of non-cytotoxic drugs. However, the role of lean body mass in predicting drug clearance for any cytotoxic drug has not been previously reported. Our purpose was to investigate lean body mass as a predictor of epirubicin clearance. Pharmacokinetic studies were performed in 10 patients receiving single agent epirubicin. Although preliminary, this study suggests that lean body should be further evaluated and tested in dose optimization studies.

Body Mass Index↗

PubMed1994

A longitudinal study of bacterial vaginosis during pregnancy.

OBJECTIVE: To determine the longitudinal changes in the incidence of vaginosis in pregnancy. DESIGN: A prospective study of women during pregnancy. SETTING: A District General Hospital in North-West London. SUBJECTS: Seven hundred and eighteen pregnant women attending antenatal clinics. At their first attendance and subsequently, Gram-stained vaginal smears were examined and Mycoplasma hominis and Gardnerella vaginalis were sought by culture. RESULTS: Initially, 87 (12%) women had bacterial vaginosis diagnosed on Gram-stained reading of the vaginal smears. Examination of further smears, obtained from 176 women at 36 weeks of gestation, showed that those whose vaginal flora was normal initially, and who went to term, rarely developed vaginosis (three of 127, 2.4%). Samples were obtained at 36 weeks gestation from 32 women who had bacterial vaginosis initially, and went to term. In almost 50% (15 of 32) of these a normal lactobacillus-dominated flora had regenerated. Thirty-five women (5%) had initial vaginal smears graded as intermediate. From this group, six of the 17 (35%) women from whom samples were obtained at 36 weeks gestation still had flora of an intermediate pattern; 10(59%) now had normal flora and only one (6%) had developed bacterial vaginosis. Women with bacterial vaginosis were more likely to be culture-positive for M. hominis than those with normal flora (34/78 versus 10/563, odds ratio 42.73 (18.9 to 102.3) P < 0.001), or to be culture-positive for G. vaginalis than those with normal flora (35/78 versus 21/563, odds ratio 21.0 (10.75 to 41.2) P < 0.001). CONCLUSION: Pregnant women do not commonly develop bacterial vaginosis after 16 weeks gestation, and if present, it remits spontaneously in approximately half of those who reach term. As bacterial vaginosis is associated with increased rates of second trimester miscarriage and preterm delivery, any treatment aimed at its eradication in pregnancy should be given no later than the beginning of the second trimester of pregnancy.

Adult↗

PubMed1994

Lean body mass as a predictor of drug dosage. Implications for drug therapy.

There is mounting evidence to suggest that lean body mass (LBM) may be a better predictor of drug dosage than either total bodyweight (TBW) or body surface area (BSA), although the rationale for this is not clear. LBM, which is similar but not identical to fat-free mass, can be determined by many different methods. A simple equation based on TBW and height, or determination by bioelectrical impedance are probably the most suitable for use in drug disposition studies. Volume of distribution of relatively hydrophilic drugs correlates very well with LBM, with correlation coefficients of up to 0.9. LBM can be used to accurately predict the loading dose required for these drugs to attain a target peak plasma concentration. For lipophilic drugs, volume of distribution correlates better with TBW than with LBM. Investigation of the relationship between renal drug clearance and LBM has received little attention, probably because creatinine clearance is a useful and readily available marker of renal function. However, limited data suggest that creatinine clearance and LBM together may account function. However, limited data suggest that creatinine clearance and LBM together may account for more variability in renal clearance than creatinine clearance alone. For many drugs eliminated predominantly by the liver, there is a good correlation between systemic clearance and LBM. Such a correlation could be due to a correlation between systemic clearance and liver size or liver blood flow, which has been demonstrated for a few drugs, and a correlation between LBM and liver size and blood flow. The presence of a relationship between LBM and organ size and blood flow has, however, not been investigated to date. A good correlation between drug clearance and LBM indicates that LBM may be an accurate predictor of maintenance dosage, especially in obese patients, in whom there is a large discrepancy between LBM and TBW. BSA is an accurate predictor of drug dosage in infants and children, but whether LBM is superior to BSA in this population remains to be determined. In most studies in adults in which dosage based on LBM has been evaluated prospectively, LBM has been shown to be superior to other measures of body size as a predictor of drug dosage.

Aging↗

PubMed1994

Albumin decreases myocardial permeability of unbound quinidine in perfused rat heart.

With the single-pass, isolated, perfused rat heart preparation, we examined the effect of different perfusate albumin concentrations on the capillary permeability and pharmacodynamic effects of quinidine. Nine hearts were perfused for five consecutive 35-min phases with buffer containing quinidine and albumin concentrations of 0%, 0.1%, 1%, 6% and 0%, in that order, with a 55-min washout between each phase. Compared with 0% albumin perfusate, the equilibrium rate of quinidine perfusate output concentration (Cout) was slower with 0.1% albumin but faster with 1% and 6% albumin. Quinidine Cout, unbound fraction (fu) and perfusion flow rate (Q) for each phase of each experiment were fitted by a modified Kety-Renkin-Crone equation. Estimates of the capillary permeability-surface product (PS) for the two 0% albumin phases (14.4 +/- 5.6 and 12.3 +/- 4.4 ml/min) were significantly higher than those for the three albumin phases (5.3 +/- 1.0, 6.7 +/- 1.2 and 7.4 +/- 2.2 ml/min, respectively; P < .05). There was a direct, linear relationship between lengthening of the QT interval of the ECG and total and unbound quinidine concentrations, but the relationship for unbound concentration was independent of fu, showing that the pharmacodynamic effect was mediated by unbound concentration. In four additional experiments with antipyrine instead of quinidine, PS for the two 0% albumin phases (24.7 +/- 6.5 and 23.2 +/- 2.4 ml/min) was not significantly different than that for the three albumin phases (25.5 +/- 6.1, 22.5 +/- 2.9 and 22.9 +/- 3.6 ml/min, respectively). Albumin had no effect on the volume of distribution referenced to unbound drug for either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effect of alpha 1-acidglycoprotein on myocardial uptake and pharmacodynamics of quinidine in perfused rat heart.

The myocardial uptake and pharmacodynamics of quinidine were examined in the isolated perfused rat heart preparation under conditions of varying concentrations of bovine alpha 1-acidglycoprotein (AAG) in the perfusate. Three hearts were perfused for five consecutive 35 min phases with buffer containing quinidine and AAG in concentrations of 0, 0.1, 0.5, 1.5 and 0 g/L, in that order, with a 55 min washout period between each phase. The equilibration rate constant for the quinidine output concentration increased with increasing AAG concentration, but not as much as predicted by the conventional pharmacokinetic uptake model, which assumes constant capillary permeability among the phases. Estimates of the permeability surface product for the two zero AAG phases (17.7 +/- 1.91 and 19.1 +/- 0.82 mL/min/g) were significantly greater than those for the three AAG phases (8.94 +/- 0.99, 8.70 +/- 0.26, 9.01 +/- 0.26 mL/min/g; P < 0.05). This effect of AAG is the same as that observed previously by us with bovine serum albumin in this same experimental preparation. This suggests that the mechanism of reduced capillary permeability is the same for both proteins, i.e., the formation of a steric barrier to paracellular transport rather than an electrostatic barrier. There was a direct, linear relationship between lengthening of the QT interval of the electrocardiogram and total and unbound quinidine concentrations, but the relationship for unbound concentration was independent of quinidine unbound fraction. Therefore, the electrocardiogram effect of quinidine was directly related to the circulating unbound rather than total drug concentration.

Animals↗

PubMed1993

Simple direct injection high-performance liquid chromatographic method to determine quinidine in plasma.

High-performance liquid chromatographic methods that use direct injection of plasma include column-switching procedures, modified mobile phases and small-pore modified stationary phases. By using a large-pore (300 A) Selectosil C18 column, developed for the analysis of macromolecules, we have shown that quinidine in plasma and protein solutions can be assayed accurately and rapidly by directly injecting 2 microliters plasma or protein solution onto the column. Column life is not reduced, and the limit of quantitation is 0.01 microM.

Animals↗

PubMed1993

The effect of hypoxia on propranolol clearance during antegrade and retrograde flow in the isolated perfused rat liver preparation.

We investigated, using the single-pass isolated perfused rat liver preparation, whether the centrilobular location of hepatic oxidative drug metabolism could be a contributing factor to the marked sensitivity of drug oxidation to hypoxia. Livers (N = 7) were each perfused for 130 min with 2 micrograms/mL (+)-propranolol, a drug metabolized almost entirely by oxidation in the rat. The direction of flow was reversed after 60 min, the order of flow direction being randomized. Normal oxygenation was used during the first 30 min of antegrade and of retrograde perfusion, but in the second 30 min perfusate was equilibrated with a N2/O2 mixture designed to reduce hepatic oxygen delivery by half. During normal oxygenation there was no significant difference between antegrade and retrograde perfusion in hepatic oxygen delivery and physiological parameters such as oxygen consumption and extraction, perfusion pressure and bile flow. During hypoxia, mean oxygen delivery was slightly lower with retrograde perfusion (retrograde: mean = 2.37 mumol/min/g liver, range = 1.56-3.17; antegrade: mean = 2.90 mumol/min/g liver, range = 1.96-4.08; P = 0.04), but there was no significant difference in physiological parameters within each liver (P > 0.05). Propranolol clearance during normal oxygenation was similar to the perfusion rate (10 mL/min) and was the same for both directions of perfusion (antegrade 9.88 +/- 0.07 mL/min, retrograde 9.88 +/- 0.13 mL/min, P > 0.05). Hypoxia reduced propranolol clearance substantially, but the decrease was significantly greater with antegrade perfusion (5.65 +/- 1.89 mL/min) than with retrograde perfusion (6.76 +/- 1.95 mL/min, P = 0.014). Oxidative drug metabolism is located primarily in the centrilobular zone and sinusoidal oxygen concentration is lowest in the "downstream" zone with both antegrade and retrograde perfusion. These findings suggest that the centrilobular location of propranolol metabolism may influence the effect of hypoxia on propranolol elimination, but is not a major contributor to the marked sensitivity of propranolol elimination to hypoxia antegrade perfusion.

Animals↗

PubMed1993

The effect of hypoxia and acidosis on propranolol clearance in the isolated perfused rat liver preparation.

The effect of hypoxia and acidosis on the elimination of an oxidatively metabolized drug, S-propranolol, was examined in the single-pass isolated perfused rat liver (IPRL). The experiments (N = 6) consisted of four consecutive 30 min phases: normal pH (pH 7.4)/normal oxygen delivery, normal pH/hypoxia, hypercapnic acidosis (pH 7.1)/normal oxygenation and hypercapnic acidosis/hypoxia. Hypoxia and acidosis were produced by equilibrating the perfusate with appropriate mixtures of O2, N2 and CO2. With normal oxygen delivery there was no difference in hepatic clearance of propranolol between normal pH and acidosis (9.65 +/- 0.34 and 9.78 +/- 0.11 mL/min, respectively. P < 0.05). During hypoxia, propranolol clearance was impaired to a similar extent under both pH conditions (7.41 +/- 0.97 and 8.06 +/- 0.81 mL/min, respectively, P > 0.05). Therefore, respiratory acidosis does not affect the clearance of propranolol by the IPRL, nor does it influence the sensitivity of propranolol clearance to hypoxia. Neither acidosis nor hypoxia resulted in a significant reduction in bile flow compared with the normal pH/normal oxygen phase and there was no correlation between bile flow and perfusate bicarbonate concentration (P > 0.05).

Acidosis, Respiratory↗

PubMed1993

Influence of albumin on isoprenaline and propranolol effects on isolated rat uterus.

We investigated the effect of albumin (6%) on the (+/-)-isoprenaline-induced relaxation of strips of isolated rat uterus and its antagonism by (-)-propranolol. The mean isoprenaline EC50 in the presence of albumin was significantly less than that in the absence of albumin (geometric mean 1.94 +/- 3.33 versus 3.21 +/- 3.50 nM, respectively; n = 14; p = 0.006, paired t test). This indicates enhancement of isoprenaline activity by albumin which could not be explained by protein binding, as this would have reduced activity. Geometric mean control KB values for inhibition of isoprenaline by propranolol at 26.8 and 500 nM were 0.835 +/- 1.68 (n = 10) and 0.889 +/- 1.60 nM (n = 34), respectively. In the presence of 6% albumin, KB for propranolol was increased significantly to 13.3 +/- 1.8 nM (n = 27, p < 0.001). Calculation of KB in terms of the measured propranolol unbound concentration of 26.8 nM, after taking into account the lower isoprenaline EC50 in the presence of albumin, yielded a mean value of 0.725 +/- 1.86 nM, which was not significantly different from either control (p > 0.05). Therefore, propranolol activity was as predicted by the unbound drug concentration in contrast to isoprenaline activity. We conclude that albumin can alter in vitro drug activity by mechanisms in addition to the reduction of unbound drug concentration.

Animals↗

PubMed1993

Protection of three strains of mice against lethal influenza in vivo by defective interfering virus.

This report examines the protective effects of defective interfering (DI) WSN on three strains of mice (C3H/He-mg (H-2k), C57BL/6 (H-2b) and BALB/c (H-2d)) infected with various doses of A/WSN influenza virus. All three strains were protected in terms of morbidity and mortality, to varying extents, DI WSN protected optimally against a low but lethal dose of A/WSN in C3H/He-mg mice, but also protected this and other strains against very high doses of A/WSN. Intermediate sized inocula gave little, if any, protection. In all cases protection required an active DI genome since inactivation with beta-propiolactone abrogated any sparing effect. Consolidation of the lungs was reduced by treatment with active DI virus, but at some doses of inoculum there was reduction in lung pathology without reduction of mortality. Treatment of infected mice with DI virus did not reduce the lung virus titre, but in C3H/He-mg mice resulted in recovery of infectious virus from other tissues, notably the heart, where it was not normally found. No infectivity was recovered from brain, liver or serum. Haemagglutination-inhibiting (HI) antibody could not be detected in the lungs of any of the infected mice co-inoculated with the control BPL-inactivated DI WSN but was present in considerable amounts in all three strains when these were co-inoculated with DI virus. These and previous data (Morgan and Dimmock, 1992) suggested that influenza virus was immunosuppressive and that active DI virus abrogated these suppressive effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Effect of plasma protein binding on kinetics of capillary uptake and efflux.

We examined the effect of plasma protein binding on the kinetics of organ accumulation and washout of drugs using the single-pass Kety-Renkin-Crone capillary model. An equation relating the accumulation and washout rate constant (k) with the plasma unbound fraction (fu) was derived. Simulations showed that k was highly dependent on fu if capillary permeability was high but was independent of fu if permeability was low. The effect of plasma protein binding was to increase the rate of tissue accumulation and washout of drug but to decrease the equilibrium amount of drug taken up by the tissue, both effects mediated via a decrease in the volume of distribution. This model was used to analyze published data on the effect of plasma protein binding on the kinetics of accumulation and washout of isradipine and propafenone in the isolated perfused heart preparation. The relationship between k and fu and the directly measured volume of distribution were in accordance with the model. Although more complex models relating k and fu could be proposed, taking into account unequal flows in capillaries, slow dissociation of ligand from protein, and unstirred layer constraints, this simple model appears adequate for describing the effect of fu on myocardial accumulation and washout of isradipine and propafenone.

Absorption↗