title: Malaria infection impairs glucuronidation and biliary excretion by the isolated perfused rat liver.
abstract: 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.
authors.affiliation: Department of Medicine, University of Melbourne, Repatriation Hospital, Australia.
authors.forename: R T
authors.initials: RT
authors.lastname: Murdoch
authors.forename: H
authors.initials: H
authors.lastname: Ghabrial
authors.forename: G W
authors.initials: GW
authors.lastname: Mihaly
authors.forename: D J
authors.initials: DJ
authors.lastname: Morgan
authors.forename: R A
authors.initials: RA
authors.lastname: Smallwood
mesh_terms: D000420:Albuterol / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001646:Bile / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology; D005965:Glucuronates / Q000378:metabolism*; D006247:Harmine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008288:Malaria / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010962:Plasmodium berghei; D011433:Propranolol / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D013656:Taurocholic Acid / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D005965:Glucuronates; D004364:Pharmaceutical Preparations; C001326:harmol; D006247:Harmine; D013656:Taurocholic Acid; D011433:Propranolol; D000420:Albuterol