The effect of diet and phenobarbitone on quinine metabolism in the rat and in man

Saggers, V. H.; Hariratnajothi, N.; McLean, A. E. M.

doi:10.1016/0006-2952(70)90206-6

Cited by 19 publications

(7 citation statements)

References 4 publications

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“…The change in ratios together with the absence of linearity in the logarithmic decay of plasma QB concentration suggests impaired metabolism of quinine in malaria. Since we did not observe a similar pattern of change in renal excretion of quinine during malaria and since the liver appears to be the major site of quinine metabolism in man, 17 altered hepatic metabolism of quinine probably accounts for the differences observed.…”

Section: Discussioncontrasting

confidence: 54%

Quinine disposition during malaria and during induced fever

Trenholme

Williams

Rieckmann

et al. 1976

Clin Pharma and Therapeutics

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Quinine disposition was studied in 5 subjects before and during an experimentally induced infection with a chloroquine-resistant strain of Plasmodium falciparum and in 2 individuals before and during artificially induced fever. Plasma quinine levels were determined by both a benzene extraction method (QB), which measures principally unmetabolized quinine, and a metaphosphoric acid precipitation method (QMPA), which measures quinine and quinine metabolites. The ratio QB/QMPA in plasma was used to estimate the extent of metabolism of quinine. In all individuals plasma levels of quinien and QB/QMPA ratios were increased during malaria, suggesting impaired hepatic metabolism of quinine. The changes observed during malaria were not due to altered renal excretion of quinine. In 2 subjects in whom fever was artificially induced there were similar changes in quinine metabolism. These observations suggest that quinine dosage should be modified during the initial period of treatment, when symptoms and fever are greatest, in acute falciparum malaria.

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Section: Discussioncontrasting

confidence: 54%

Quinine disposition during malaria and during induced fever

Trenholme

Williams

Rieckmann

et al. 1976

Clin Pharma and Therapeutics

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“…Probably the most widely studied interaction of barbiturates is with oral anticoagulants. For example, concurrent administration of phenobarbitone and warfarin to patients produced changes in steady-state plasma warfarin and anticoagulant effect within 6 days; the Hildebrandt et al (1975) Vesell and Page (1969) Cucinell et al (1965) Forrest et al (1970 Burstein and Klaiber (1965) Hammer and Sioqv!st (19B7) Viala et al (1971) Solomon and Abrams (1972) Neuvonen and Pentilla (1974) Helleberg et al (1974) Busfield et al (1963) Bogaert et al (1971\ Hempel et al (1973 Whittaker and Price-Evans (1970) Cucinell et al (1965) Saggers et al (1970) Southren et al (1969 Breckenridge and Orme (1971) De Rautlin de la Roy et al (1971) maximum effect is usually seen after 14 to 21 days (fig 2; Breckenridge and Orme, 1971). After withdrawal of phenobarbitone, drug metabolism returns to normal and this may lead to fatal haemorrhage during continued anticoagulant therapy (MacDonald and Robinson, 1968).…”

Section: Phenobarbitone (Phenobarbital)mentioning

confidence: 97%

Clinical Implications of Enzyme Induction and Enzyme Inhibition

Park

Breckenridge

1981

Clinical Pharmacokinetics

159

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The pharmacological effect of a drug is partly dependent upon its concentration at its site of action, which in turn is partly dependent upon its rate of elimination. The rate of elimination of many lipophilic drugs is governed by the activity of the hepatic microsomal mixed-function oxidases. Consequently any alteration in the activity of these enzymes may result in a modification of drug action. A wide range of chemically unrelated substances may stimulate the activity of the mixed-function oxidases by enzyme induction. The drugs most frequently encountered as enzyme-inducing agents in man are barbiturates, rifampicin and phenytoin. Enhancement of drug metabolism by ethanol, tobacco smoking and diet may also involve enzyme induction. Enzyme induction is normally associated with a reduction in the drug efficacy but may also alter the toxicity of certain substances. Enzyme induction has been assessed in man by measuring changes in the pharmacokinetics of a marker drug, or changes in the disposition of endogenous compounds such as gamma-glutamyltranspeptidase, D-glucaric acid and 6beta-hydroxycortisol. The therapeutic problems associated with enzyme inhibition have received much less attention than those associated with enzyme induction. The effect on the rate of elimination of a particular drug will depend upon the fraction of the dose that is normally metabolised by the inhibited enzyme and on the affinity of the enzyme for the drug and the inhibitor. An alteration in the dosage schedule is usually only necessary for drugs with a small therapeutic ratio.

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“…Rabbit, guinea pig, and rat livers were able to metabolize quinine readily and even at a high rate [38]. Rabbit, guinea pig, and rat livers were able to metabolize quinine readily and even at a high rate [38].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Hepatic Metabolism of Cyp3a-Mediated Drugs Quinine and Midazolam in the Common Brush-Tailed Possum (Trichosurus Vulpecula)

Ho¹,

Luo²,

Macauley³

et al. 1998

Environ Toxicol Chem

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This report characterizes the P450 isoenzymes involved in quinine metabolism in liver microsomes of the common brush‐tailed possum (Trichosurus vulpecula). The mean maximal velocity (Vmax) for 3‐hydroxyquinine formation in possum livers was 1,512 ± 510 pmol/mg protein/min (males) and 1,680 ± 690 pmol/mg protein/min (females). The mean Vmax value for 3‐hydroxyquinine formation in possums was approximately threefold higher than that found in human livers. The mean apparent Michaelis constant (Km) for 3‐hydroxyquinine formation in possum livers was 31.9 ± 16 μM in males and 16.1 ± 5 μM in females. At low concentrations of quinine (40 μM), the quinine 3‐hydroxylation was inhibited more than 90% by midazolam, 60% by troleandomycin, 40% by erythromycin, and 47% by nifedipine, all of which are CYP3A inhibitors. Other inhibitors for CYP2C9/10, CYP2D6, CYP2E1, and CYP1A1/2 showed little or no inhibition effect on 3‐hydroxylation of quinine. Xenobiotic inhibition studies suggest that the liver CYP3A enzyme family or one similar to human liver CYP3A is responsible for 3‐hydroxylation of quinine in possum livers. The metabolism of midazolam to 1′‐hydroxy and 4‐hydroxy metabolites was also studied. The in vitro metabolism of midazolam was found to be much lower in possum liver microsomes as compared to that observed in human liver microsomes. The mean Vmax values for 4‐hydroxy‐ and 1′‐hydroxymidazolam in male possums were 179 ± 53 and 479 ± 333 pmol/mg protein/min, respectively. For female possums, the mean Vmax values were 235 ± 31 and 671 ± 143 pmol/mg protein/min, respectively. These Vmax values for male possums were 23 and 8 times less (17 and 6 times less for female possums), respectively, than those observed with human liver microsomes. The present study has demonstrated that, although possums are able to metabolize both midazolam and quinine, the capacity to metabolize midazolam is considerably lower in possum livers than in human livers. This finding could be useful for the selection of alternative poisons to control populations of possums.

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The effect of diet and phenobarbitone on quinine metabolism in the rat and in man

Cited by 19 publications

References 4 publications

Quinine disposition during malaria and during induced fever

Quinine disposition during malaria and during induced fever

Clinical Implications of Enzyme Induction and Enzyme Inhibition

In Vitro Hepatic Metabolism of Cyp3a-Mediated Drugs Quinine and Midazolam in the Common Brush-Tailed Possum (Trichosurus Vulpecula)

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