Effect of malaria infection on the pharmacokinetics of paracetamol in rat

Ismail, Suzylawati; Kokwaro, Gilbert; Back, David; Edwards, Geoffrey

doi:10.3109/00498259409043255

Cited by 11 publications

(6 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since urine flow and excretion of parace-tamol glucuronide were not influenced by malaria, the formation clearance of paracetamol glucuronide was not significantly different between the two study phases. This is in contrast to the results obtained in rat in vivo [6] where experimentally-induced malaria significantly decreased the glucuronidation of paracetamol. The disparity could be due to differences in the severity of infection or in the availability of uridine diphosphoglucuronic acid (UDPGA), a critical co-factor in hepatic glucuronidation.…”

Section: Discussioncontrasting

confidence: 56%

“…Studies to date have examined the effect of experimental malaria (Plasmodium berghei) infection on Phase II conjugation reactions in animal models. Most of these [1,2,3,4,5,6] have shown a consistent decrease in glucuronidation in malaria with sulphation being largely unaltered.…”

Section: Discussionmentioning

confidence: 99%

“…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. Previous work [5,6] Paracetamol is selected because it is extensively metabolized by the liver. An oral dose of 1000 mg is excreted mostly as glucuronide (55 %) and sulphate conjugates (30 %) with only 2 to 5 % excreted unchanged in the urine [7].…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Ismail

Back

Edwards

et al. 1995

Eur J Clin Pharmacol

Self Cite

View full text Add to dashboard Cite

Investigations in animals have suggested that conjugation of paracetamol may be reduced in malaria. We have measured plasma concentrations and the urinary excretion of paracetamol and its phase II metabolites in eight Thai patients during uncomplicated falciparum malaria and in convalescence, following a 1000 mg single oral dose. The apparent oral clearance (Malaria, 3.6; Convalescence, 3.9; ml.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; l.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.

show abstract

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Ismail

Back

Edwards

et al. 1995

Eur J Clin Pharmacol

Self Cite

View full text Add to dashboard Cite

show abstract

“…UGTs are membrane-bound enzymes located in the endoplasmic reticulum and, according to the conformation hypothesis for regulation of UGT, require re-arrangement of their three-dimensional structure for activation (Mulder, 1992;Burchell & Coughtrie, 1989;Zakim & Dannenberg, 1992). Hence, structural changes to cellular organelles that occur in MI (Rosen et al, 1967) might decrease UGT activity and reduce glucuronidation (Glazier et al, 1994;Ismail et al, 1994). Speculation on the cause of impaired glucuronidation in our experiments is beyond the scope of this report.…”

Section: Discussionmentioning

confidence: 71%

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

View full text Add to dashboard Cite

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.

show abstract

“…Murdoch et al [44], however, evaluated phenol conjugation in perfused rat livers and noted that P.berghei infection decreased phenol glucuronide formation. Along the same line, Ismail et al [45] described that malaria impaired glucuronidation of paracetamol in rats in vivo. In both cases, ex vivo and in vivo reductions in phenol and paracetamol glucuronidations may have been due to a lower availability of the co-substrate uridine diphosphoglucuronic acid (UDPGA) in the liver of infected rats.…”

Section: Discussionmentioning

confidence: 93%

Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

De-Oliveira

Carvalho

Paixao

et al. 2010

Malar J

View full text Add to dashboard Cite

BackgroundThe mechanisms by which malaria up and down-regulates CYP activities are not understood yet. It is also unclear whether CYP activities are modulated during non-lethal malaria infections. This study was undertaken to evaluate the time course of CYP alterations in lethal (Plasmodium berghei ANKA) and non-lethal (Plasmodium chabaudi chabaudi) murine malaria. Additionally, hypotheses on the association of CYP depression with enhanced nitric oxide (NO) production, and of CYP2a5 induction with endoplasmic reticulum dysfunction, enhanced haem metabolism and oxidative stress were examined as well.MethodsFemale DBA-2 and C57BL/6 mice were infected with P.berghei ANKA or P. chabaudi and killed at different post-infection days. Infection was monitored by parasitaemia rates and clinical signs. NO levels were measured in the serum. Activities of CYP1a (ethoxyresorufin-O-deethylase), 2b (benzyloxyresorufin-O-debenzylase), 2a5 (coumarin-7-hydroxylase) and uridine-diphosphoglucuronyl-transferase (UGT) were determined in liver microsomes. Glutathione-S-transferase (GST) activity and concentrations of gluthatione (GSH) and thiobarbituric acid-reactive substances (TBARS) were determined in the liver. Levels of glucose-regulated protein 78 (GRP78) were evaluated by immunoblotting, while mRNAs of haemoxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) were determined by quantitative RT-PCR.ResultsPlasmodium berghei depressed CYP1a and 2b and induced 2a5 in DBA-2 mice. In P.berghei-infected C57BL/6 mice CYP activities remained unaltered. In both strains, GST and UGT were not affected by P.berghei. Plasmodium c. chabaudi depressed CYP1a and 2b and induced 2a5 activities on the day of peak parasitaemia or near this day. CYP2a5 induction was associated with over-expression of HO-1 and enhanced oxidative stress, but it was not associated with GRP78 induction, a marker of endoplasmic reticulum stress. Plasmodium chabaudi increased serum NO on days near the parasitaemia peak in both strains. Although not elevating serum NO, P.berghei enhanced iNOS mRNA expression in the liver.ConclusionDown-regulation of CYP1a and 2b and induction of 2a5 occurred in lethal and non-lethal infections when parasitaemia rates were high. A contribution of NO for depression of CYP2b cannot be ruled out. Results were consistent with the view that CYP2a5 and HO-1 are concurrently up-regulated and suggested that CYP2a5 induction may occur in the absence of enhanced endoplasmic reticulum stress.

show abstract

Effect of malaria infection on the pharmacokinetics of paracetamol in rat

Cited by 11 publications

References 18 publications

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

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

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

Up- and down-modulation of liver cytochrome P450 activities and associated events in two murine malaria models

Contact Info

Product

Resources

About