Differential Effects of Hypoxia on the Disposition of Propranolol and Sodium Taurocholate by the Isolated Perfused Rat Liver

Jones, D. E.; Mihaly, G W; Smallwood, Richard A.; Webster, Lorraine K.; Morgan, Denis J.; Madsen, N.P.

doi:10.1002/hep.1840040319

Cited by 41 publications

(15 citation statements)

References 20 publications

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“…We have shown previously that these two compounds do not affect each other's elimination at the physiological concentrations of taurocholate used (Jones et al 1984).…”

Section: Discussionmentioning

confidence: 98%

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver

et al. 1991

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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.

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“…We have shown previously that these two compounds do not affect each other's elimination at the physiological concentrations of taurocholate used (Jones et al 1984).…”

Section: Discussionmentioning

confidence: 98%

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver

et al. 1991

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“…[55,56] These discrepancies could be due to differences in disease aetiologies, disease severity or doses given, and also to the use of indocyanine green as a marker of liver function. Indocyanine green undergoes biliary excretion, a process that does not use oxygen directly, [57] and therefore would not be expected to accurately reflect changes in oxidative drug metabolism resulting from increased hepatic oxygenation.…”

Section: The Oxygen Limitation Theorymentioning

confidence: 99%

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Morgan

McLean

1995

Clinical Pharmacokinetics

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193

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The effects of liver disease on pharmacokinetics and pharmacodynamics are highly variable, and difficult to predict as the mechanisms of these effects are not well understood. Since the majority of the published literature is concerned with cirrhotic liver disease, this review also focuses mainly on this area. Four different theories have been proposed to account for the effects of chronic liver disease with cirrhosis on hepatic drug elimination: the sick cell theory; the intact hepatocyte theory; the impaired drug uptake theory; and the oxygen limitation theory. While some data in support of each of the first 2 theories have been published recently, a large amount of clinical data would appear to refute both of these theories. These clinical data are substantially consistent with the latter 2 theories, which regard the decreased permeability of the capillarised sinusoid as the critical feature in cirrhosis. Further work is required to determine the applicability of each of these theories. In cirrhosis, drug glucuronidation is spared relative to oxidative drug metabolism; however, in advanced cirrhosis this pathway may also be impaired substantially. There is evidence that in cirrhosis other conjugation pathways may also be impaired to variable degrees. Growing evidence suggests that biliary drug excretion is impaired in cirrhosis. Recent studies with several racemic drugs indicate that the disease can have different effects on the hepatic elimination of individual enantiomers, which may lead to a change in the concentration-response relationships of racemic drugs in cirrhosis. A major finding which has emerged in recent years is that, even with moderate degrees of hepatic impairment, there is a decrease in clearance of drugs or active metabolites normally cleared by the kidney. The effect on renal clearance of unbound drug may be masked if there is a concomitant decrease in plasma protein binding of the drug. Neither serum creatinine levels nor creatinine clearance are useful markers of the renal dysfunction associated with cirrhosis. Both may greatly overestimate renal function in patients with cirrhosis due to increased fractional renal tubular secretion of creatinine. Altered receptor sensitivity has been observed with some drugs in cirrhosis, while for other drugs there is no change in pharmacodynamics. Precise determination of drug dosage in cirrhosis requires information on changes in pharmacodynamics and plasma protein binding in addition to changes in drug elimination. Pharmacokinetic investigations in a variety of chronic liver diseases without cirrhosis (e.g. carcinoma, schistosomiasis and viral hepatitis) suggest that in the absence of cirrhosis, impairment of drug elimination is not sufficient to warrant reduction of drug dosage. However, if cirrhosis is present, 'safe' drug use requires an awareness of the possibility of multiple interactions between changes in hepatic and renal disposition and pharmacodynamics. In chronic liver disease with cirrhosis, dosage reduction is the general rule regardless...

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“…Rats were anaesthetised with sodium pentobarbitone (60 ± 120 mg kg 71 ) and IPRL preparations were established according to standard techniques (Miller, 1973;Jones et al, 1984;Mihaly et al, 1987;Mansor et al, 1990 (63) with an equal volume of 0.9% sodium chloride solution, followed by centrifugation at 1200 g for 10 min (48C) and aspiration of the supernatant and buy coat.…”

Section: Isolated Perfused Rat Liver (Iprl) Preparationmentioning

confidence: 99%

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Batty

Ilett

Edwards

et al. 1998

British J Pharmacology

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1 The clearance of dihydroartemisinin (DHA) in control and malaria-infected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2 In the recirculating IPRL, clearance of DHA was reduced from a mean (s.d.) of 8.2+1.8 ml min 71 in controls (n=8) to 6.0+1.0 ml min 71 in MI (n=8; P50.01). Clearance in control livers was similar to the perfusion¯ow rate, suggesting a high hepatic extraction ratio for DHA. 3 Single-pass IPRL studies in controls (n=8) showed that DHA bioavailability at 1.3, 8 and 38 mM was 0.026+0.020, 0.043+0.025 and 0.14+0.06, respectively (P50.001 for 8 mM vs 38 mM). In MI livers (n=5), DHA bioavailability at 8 and 38 mM was 0.18+0.07 and 0.40+0.08, respectively (P=0.002). Bioavailability was higher in the MI group than in controls (P=0.01 at 8 mM and P50.001 at 38 mM). DHA-glucuronide was the sole biliary metabolite. 4 Hepatic microsomal studies of DHA-glucuronide formation showed a signi®cantly lower V max , but no signi®cant change in K m , in MI compared to control livers (n=6). Intrinsic metabolic clearance (V max /K m ) was higher in control than in MI livers (5.2+1.3 and 2.5+1.4 ml min 71 mg 71 , respectively; P=0.006). 5 These studies demonstrate that DHA has a high, concentration-dependent hepatic extraction ratio that is reduced by 20 ± 30% in the P. berghei rodent malaria model. The impaired hepatic clearance of DHA in MI is attributable to a reduction in intrinsic metabolic clearance.

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Differential Effects of Hypoxia on the Disposition of Propranolol and Sodium Taurocholate by the Isolated Perfused Rat Liver

Cited by 41 publications

References 20 publications

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver

Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver

Clinical Pharmacokinetic and Pharmacodynamic Considerations in Patients with Liver Disease

Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

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