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.

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

“…Oxygen consumption in control IPRLs was similar throughout the experiments, albeit slightly lower than in some previous studies (normally at least 1.9 mmol O 2 min 71 g 71 liver (Gores et al, 1986;Cheung et al, 1996)). As in previous reports (Mansor et al, 1990;Murdoch et al, 1991Murdoch et al, , 1992, indices of liver viability were aected by MI, with bile¯ow and oxygen consumption signi®cantly lower in MI compared to control livers (Tables 1 and 2). Overall, these data con®rm that the experimental conditions for our IPRL studies were acceptable.…”

“…Since MI and control livers had comparable cellular volumes, it was likely that metabolic rather than structural changes to the liver were responsible for impaired clearance of DHA. MI is known to decrease the cytochrome P450 content in rat liver microsomes (McCarthy et al, 1970) and has been shown in the IPRL model to reduce the clearance of several drugs, including the quinoline antimalarials and xenobiotics that are metabolised by glucuronidation (Mihaly et al, 1987;Mansor et al, 1990;Murdoch et al, 1991Murdoch et al, , 1992Glazier et al, 1994). Biliary clearance of DHA-glucuronide, the principal biliary metabolite of DHA (Maggs et al, 1997), also was impaired in MI (Table 3).…”

“…In addition, in vitro studies using the isolated perfused rat liver (IPRL) model have shown that MI decreases hepatic clearance of quinoline drugs (Mihaly et al, 1987;Mansor et al, 1990). Furthermore, the IPRL model has been used to demonstrate that MI signi®cantly impairs glucuronide conjugation of several xenobiotics, including paracetamol, salbutamol, harmol and phenol (Murdoch et al, 1991(Murdoch et al, , 1992Glazier et al, 1994).…”

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

“…Studies in humans and experimental rodent models have reported malaria-induced alterations in the hepatic metabolism and clearance of numerous drugs, including many that are used in the treatment of malaria (Mihaly et al, 1987;Mansor et al, 1990;Murdoch et al, 1991;Pukrittayakamee et al, 1997). In mice, malaria infection is associated with decreases in the hepatic expression of CYP3A11 and other drug metabolizing enzymes (DMEs) (De-Oliveira et al, 2006;Carvalho et al, 2009).…”

Paracetamol disposition in Thai patients during and after treatment of falciparum malaria

“…min -1. kg-1), the elimination half-life (Malaria, 3.8; Convalescence, 3.7 h) and apparent volume of distribution (Malaria, 1.2; Convalescence, 1.2; 1. kg -1) of paracetamol were similar during malaria and convalescence. In addition, the urinary excretion of paracetamol and its major phase II metabolites and their formation clearances from paracetamol were not significantly different between the two study phases.These data show that clinical malaria infection has no effect on the conjugation of paracetamol in man.Key words Paracetamol, Malaria; pharmacokinetics, phase II conjugation, glucuronidation, sulphation Hepatic phase II conjugation reactions are known to be reduced by experimental malaria infections in animals and perfused organ systems [1,2,3,4]. The aim of this investigation was to study the influence of clinical malaria on phase II conjugation reactions in man using paracetamol as a probe.…”