Microsomal enzyme induction in children: the influence of carbamazepine treatment on antipyrine kinetics, 6 beta‐hydroxycortisol excretion and plasma gamma‐glutamyltranspeptidase activity.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• CYP3A4 converts cholesterol into 4b-hydroxycholesterol.• We have suggested that 4b-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments.• The kinetics of 4b-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4b-hydroxycholesterol can be used as a CYP3A marker. WHAT THIS STUDY ADDS• The concentration of 4b-hydroxycholesterol increases very slowly during CYP3A4/5 induction in paediatric patients.• Whereas induction of CYP3A4/5 was apparently complete within 1-2 weeks of carbamazepine treatment, plasma 4b-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMSTo investigate the time course of the increase in 4b-hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy. METHODSEight paediatric patients with newly diagnosed epilepsy were studied. Blood samples were drawn before and after about 1, 2, 4, 8 and 16 weeks of carbamazepine treatment. The plasma concentrations of 4b-hydroxycholesterol were determined by gas chromatography-mass spectrometry and carbamazepine and its epoxide metabolite by high-performance liquid chromatography. RESULTSThe basal plasma concentrations of 4b-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml . Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1-2 weeks after last dose change. CONCLUSIONSCarbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4b-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1-2 weeks, the increase in 4b-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4b-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

Section: Resultsmentioning

confidence: 99%

Time course of the increase in 4β‐hydroxycholesterol concentration during carbamazepine treatment of paediatric patients with epilepsy

Wide

Larsson

Bertilsson

et al. 2008

“…This finding is consistent with early papers reporting that 6,B-hydroxycortisol urinary excretion is not associated with debrisoquine polymorphism which is related to a genetic defect affecting P450IID6 gene expression (Gonzalez et al, 1988) and is not affected by polycyclic aromatic hydrocarbons (P450IA1 and P4501A2 inducers) produced by cigarette smoking (Vestal et al, 1987). On the other hand, anticonvulsants known to be inducers of the P450IIIA subfamily in vivo in laboratory animals (phenobarbitone) or in human hepatocyte cultures (phenobarbitone, carbamazepine, phenytoin, P. Maurel, unpublished observations) can also increase 61-hydroxycortisol urinary excretion in vivo in man (Park, 1981;Ohnhaus & Park, 1979;Moreland et al, 1982;Zhiri et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…This reaction was shown to be catalyzed by P450 enzymes and 6,-hydroxycortisol can be measured in urine where it is excreted unconjugated (Ohnhaus & Park, 1979). This is a minor pathway in cortisol metabolism but represents a sensitive target for inducers (Moreland et al, 1982;Perucca et al, 1988;Roots et al, 1979). Furthermore, no drug administration is necessary since cortisol is an endogenous steroid.…”

Section: Introductionmentioning

confidence: 99%

The increase in urinary excretion of 6 beta‐hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction.

Ged

Rouillon

Pichard

et al. 1989

312

156

1. Urinary excretion of 6 beta‐hydroxycortisol, hepatic microsomal cortisol 6 beta‐hydroxylase and the specific content of several forms of cytochrome P450 were measured in 8 to 14 patients before and after treatment with rifampicin (600 mg orally per day for 4 days). 2. Rifampicin treatment produced an average five fold increase in daily excretion of urinary 6 beta‐hydroxycortisol. 3. Cortisol 6 beta‐ hydroxylase activity increased from 15 +/‐ 6 pmol min‐1 mg‐1 in organ donors (considered as 'control subjects') to 87 +/‐ 31 pmol min‐1 mg‐1 in rifampicin treated patients. 4. Among three forms of human P450 (P450IA, IIC and IIIA), (1), (2), measured by Western blots, only P450IIIA was significantly induced by the antibiotic. 5. Only antibodies against P450IIIA selectively inhibited cortisol 6 beta‐ hydroxylase in human liver microsomes. 6. Cortisol 6 beta‐hydroxylase was correlated with P450IIIA specific content. 7. The urinary level of 6 beta‐hydroxycortisol correlated with liver microsomal cortisol 6 beta‐ hydroxylase and P450IIIA specific content. 8. We conclude that P450IIIA is predominantly responsible for cortisol 6 beta‐hydroxylase activity in human liver microsomes and that urinary 6 beta‐hydroxycortisol is a marker of the induction of this cytochrome P450.

“…Therapeutic doses of the antiepileptic drugs (AEDs) phenytoin (PHT), carbamazepine (CBZ) and phenobarbitone (PB) are potent hepatic enzyme (mixed function oxidase) inducers (Petruch et al, 1974;Roberts et al, 1976;Moreland et al, 1982;Rapeport et al, 1983;Park et al, 1984;Shaw et al, 1985). In contrast, sodium valproate (VPA) does not have any significant enzyme inducing properties (Oxley et al, 1979;Perucca et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Effect of the removal of individual antiepileptic drugs on antipyrine kinetics, in patients taking polytherapy.

Patsalos

Duncan

Shorvon

1988

1 Antipyrine (AP) clearance, half-life and volume of distribution were determined in 52 patients, taking one or more antiepileptic drug (AED), before and 4 weeks after the complete removal of phenytoin (PHT, n = 20), carbamazepine (CBZ, n = 15) and sodium valproate (VPA, n = 17). 2 PHT removal was associated with a mean 13% fall in AP clearance and a mean 16% increase in AP half-life, in patients who were also taking CBZ with or without barbiturates. There was no significant difference between patients who did, and did not, take barbiturates, in addition to CBZ. 3 CBZ removal was associated with a mean 45% fall in AP clearance and a mean 69% increase in AP half-life, if there was no inducing AED comedication, but had no effect on AP clearance and half-life if PHT and/or barbiturates were also being taken. 4 Removal of VPA had no effect on AP clearance or half-life. 5 The removal of PHT, CBZ and VPA had no significant effect on AP volume of distribution. 6 PHT appears to be a more powerful inducer of hepatic enzyme activity, as measured by the AP test, than is CBZ.