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1. Herbal supplements widely used in the US were screened for the potential to inhibit CYP2C8 activity in human liver microsomes. The herbal extracts screened were garlic, echinacea, saw palmetto, valerian, black cohosh and cranberry. N-desethylamodiaquine (DEAQ) and hydroxypioglitazone metabolite formation were used as indices of CYP2C8 activity. 2. All herbal extracts showed inhibition of CYP2C8 activity for at least one of three concentrations tested. A volume per dose index (VDI) was calculated to determine the volume in which a dose should be diluted to obtain IC50 equivalent concentration. Cranberry and saw palmetto had a VDI value > 5.0 l per dose unit, suggesting a potential for interaction. 3. Inhibition curves were constructed and the IC50 (mean ± SE) values were 24.7 ± 2.7 μg/ml for cranberry and 15.4 ± 1.7 μg/ml for saw palmetto. 4. The results suggest a potential for cranberry or saw palmetto extracts to inhibit CYP2C8 activity. Clinical studies are needed to evaluate the significance of this interaction.

Context: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively., Objective: In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population., Materials and Methods: In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers (n = 24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants., Results: The frequency of the CYP2A6*1B, CYP2A6*4, CYP2A6*8 and CYP2A6*9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6*1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs., Discussion: Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea (p < 0.05)., Conclusion: It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population.

1. The hepatic metabolism of the antimalarial drug amodiaquine was investigated in order to gain further insight into the postulated metabolic causation of the hepatotoxicity, which restricts the use of the drug. After intraportal (i.p.) administration (54 mumol/kg) to the anaesthetized rat, the drug was excreted in bile (23 +/- 3% dose over 5 h; mean +/- SD, n = 6) primarily as thioether conjugates. 2. After i.p. administration, 20% of the dose was excreted into urine over 24 h as parent compound and products of N-dealkylation and oxidative deamination. Desethylamodiaquine accumulated in liver, but was not a substrate for bioactivation as measured by biliary elimination of a glutathione adduct. 3. Prior administration of ketoconazole, an inhibitor of P450, reduced biliary excretion by 50% and effected a corresponding decrease in the amount of drug irreversibly bound to liver proteins. This indicated a role for P450 in the bioactivation of amodiaquine to a reactive metabolite that conjugates with glutathione and protein. 4. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. 5. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. 6. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.