Showing papers by "Leif Bertilsson published in 1997"

Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects

Abstract: Stereoselective disposition of omeprazole and its formed 5-hydroxy metabolite were studied in five poor metabolizers and five extensive metabolizers of S-mephenytoin. After a single oral dose of omeprazole (20 mg), the plasma concentrations of the separate enantiomers of the parent drug and the 5-hydroxy metabolite were determined for 10 hours after drug intake. In poor metabolizers, the area under the plasma concentration versus time curve [AUC(0-8)] of (+)-omeprazole was larger and that of the 5-hydroxy metabolite of this enantiomer was smaller than the AUC(0-8) values in extensive metabolizers (p < 0.001). The mean AUC(0-8) of the (-)-enantiomer of omeprazole was also higher in poor metabolizers than in extensive metabolizers, but only 3.1-fold compared with 7.5-fold for (+)-omeprazole. The rate of formation of the hydroxy metabolite from (-)-omeprazole was low and not significantly different in poor and extensive metabolizers. These results show that (+)-omeprazole is to a major extent hydroxylated by CYP2C19. Also (-)-omeprazole may partly be metabolized by this enzyme but is mainly metabolized by another enzyme, presumably CYP3A4, to the achiral sulfone metabolite. The plasma concentration ratio of omeprazole to 5-hydroxyomeprazole obtained 3 hours after the drug intake has been used to distinguish between extensive and poor metabolizer phenotypes. With use of the ratio between the (+)-enantiomers of the parent drug and the metabolite, a better discrimination between phenotypes was obtained. The ratio between the (-)-enantiomers also separated the phenotypes but was less discriminatory. For the future, measurement of total concentrations will suffice for phenotyping.

Pharmacogenetics of antidepressants: clinical aspects

Abstract: Plasma concentrations and response to antidepressants vary considerably between patients treated with similar dosages. Most antidepressants and also antipsychotics are metabolized by the polymorphic debrisoquine/sparteine hydroxylase, i.e., cytochrome P450 (CYP)2D6. About 7% of Caucasians are poor metabolizers (PM), and such patients might develop adverse drug reactions when treated with recommended doses of, for example, tricyclic antidepressants. In contrast, ultrarapid metabolizers with multiple CYP2D6 genes might require high doses of such drugs for optimal therapy. The mean CYP2D6 activity is lower in Oriental than in Caucasian populations, because of a frequent mutation causing decreased enzyme activity. Drugs metabolized by the same enzyme may interact with each other. For example, the potent CYP2D6 inhibitor fluoxetine increases the plasma concentrations of tricyclic antidepressants. Another enzyme catalyzing the metabolism of antidepressants is the polymorphic S-mephenytoin hydroxylase. CYP2C19, which catalyses the metabolism of, for example, citalopram, clomipramine and moclobemide. Various probe drugs may be used for phenotyping CYP2D6 (debrisoquine, dextromethorphan and sparteine) and CYP2C19 (mephenytoin and omeprazole). Allele-specific polymerase chain reaction (PCR)-based methods are now available for genotyping using leukocyte DNA. A major advantage of genotyping compared with phenotyping is that the former may be performed in blood samples from patients irrespective of treatment.

Inhibition of the sulfoxidation of omeprazole by ketoconazole in poor and extensive metabolizers of S‐mephenytoin

Abstract: Background The metabolism of omeprazole includes hydroxylation catalyzed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CYP3A4. Sulfoxidation may be the predominant pathway in individuals devoid of the genetically determined CYP2C19 activity. Ketoconazole is a known CYP3A4 inhibitor in daily doses from 200 to 400 mg. In this study ketoconazole was used as a probe to investigate the extent to which CYP3A4 is involved in omeprazole metabolism in vivo. Methods A single oral 20 mg dose of omeprazole before and after four daily doses of 200, 100, or 50 mg ketoconazole was given to 10 healthy subjects, previously phenotyped as poor or extensive metabolizers of S-mephenytoin. Concentrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, and ketoconazole were analyzed with reversed-phase HPLC methods in plasma samples collected repeatedly for 12 hours after dosing. Results After intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazole, mean values for omeprazole sulfone area under the plasma concentration versus time curve from 0 to 6 hours [AUC(0–6)] were 482, 206, 167, and <100 nmol/L · hr in extensive metabolizers and 3160, 2430, 937, and 534 nmol/L · hr in poor metabolizers, respectively. Mean omeprazole AUC(0–6) increased from 1660 to 2265 nmol/L · hr in extensive metabolizers and from 7715 to 15319 nmol/L · hr in poor metabolizers after intake of 200 mg ketoconazole. Conclusions An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers and leads to a doubling of omeprazole levels in poor metabolizers, whereas 50 mg ketoconazole provides only partial inhibition. We concluded that CYP3A4 catalyzes the sulfoxidation of omeprazole and that this is the predominant metabolic pathway of omeprazole in poor metabolizers of S-mephenytoin. Clinical Pharmacology & Therapeutics (1997) 62, 384–391; doi:

In vitro and in vivo studies on the disposition of mirtazapine in humans

Abstract: The novel antidepressant mirtazapine is a racemate with both noradrenergic and serotonergic potentiating effects. In vitro metabolism of racemic mirtazapine was studied in (a) microsomes from cells expressing different cytochrome P450 (CYP) enzymes and (b) human liver microsomes from 10 subjects and compared with the rate of metabolism of 4 substrates of specific CYP enzymes: ethoxyresorufin (CYP1A2), diclofenac (CYP2C9), bufuralol (CYP2D6) and testosterone (CYP3A4). These experiments suggested that the 8-hydroxylation of mirtazapine is catalysed by CYP2D6, and that the N(2)-demethylation and N(2)-oxidation are catalysed by CYP3A4. Mirtazapine was shown to be a competitive inhibitor of the CYP2D6 mediated hydroxylation of bufuralol in vitro, but with a 10 times higher inhibition constant (Ki) than for fluoxetine, i.e. mirtazapine is a much weaker inhibitor. To investigate the importance of CYP2D6 for the in vivo disposition of mirtazapine, a single oral dose of racemic mirtazapine was given to 7 extensive (EM) and 7 poor metabolisers (PM) of debrisoquine. Plasma concentrations (sum of enantiomers) of mirtazapine and its demethyl metabolite were monitored over 3 days. Oral plasma clearance of mirtazapine was very similar in EM and PM of debrisoquine (0.51 ±0.18 and 0.49 ± 0.22 L/h/kg, respectively; NS). In addition, the mean half-lives were almost identical: 23.4 and 23.3 hours, respectively. Plasma concentrations of demethylmirtazapine were also very similar in EM and PM. This in vivo study indicates that the major enantiomer of mirtazapine in plasma is not metabolised by CYP2D6, but it cannot be excluded that the minor one is. A study using a chiral analysis of the 2 enantiomers is currently ongoing. From a clinical point of view it is unlikely that mirtazapine would inhibit the metabolism of coadministered drugs metabolised by CYP1A2, CYP2D6 or CYP3A4. The panel study on EM and PM shows that strong inhibitors of CYP2D6 would not be expected to affect the concentration of the major mirtazapine enantiomer, but the effect on the minor enantiomer cannot be predicted.

The CYP2D6 Genotype and Plasma Concentrations of Mianserin Enantiomers in Relation to Therapeutic Response to Mianserin in Depressed Japanese Patients

Abstract: The relationship between therapeutic response to racemic mianserin and steady-state plasma concentrations of S(+)- and R(-)-mianserin was studied in 26 Japanese patients with major depression. The daily dose of mianserin was 30 mg, and the duration of treatment was 3 weeks. Regarding S-mianserin, th

Significance of monitoring plasma levels of amitriptyline, and its hydroxylated and desmethylated metabolites in prediction of the clinical outcome of depressive state

Abstract: The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 inpatients. Discriminant analysis of drug concentrations (at two weeks after initiation of drug treatment) and clinical outcome revealed that increasing the plasma levels of amitriptyline, cis-isomers of hydroxylated metabolites (Z-10-hydroxyamitriptyline and Z-10-hydroxynortriptyline) predicted a better clinical outcome, while increasing of plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites (E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline) were shown to predict a poor clinical outcome in the depressive episode of the subjects, and that clinical outcome of approximately 73% of the subjects could be correctly predicted.

An S-mephenytoin cysteine conjugate identified in urine of extensive but not of poor metabolizers of S-mephenytoin.

Abstract: A conjugate of S-mephenytoin excreted in urine of extensive but not of poor metabolizers of S-mephenytoin has previously been reported. This conjugate, which is easily hydrolysed back to S-mephenytoin, has now been isolated and identified in urine from one extensive metabolizer after a single dose of 100 mg racemic mephenytoin. High performance liquid chromatography purification, followed by gas chromatographic, mass spectrometric and amino acid analyses showed that the isolated compound is a cysteine conjugate of S-mephenytoin. The significant mass spectrometric ions have been confirmed in three additional extensive metabolizers of S-mephenytoin, but were not detectable in urine from three poor metabolizer subjects. The exact structure of the conjugate is unknown, but we suggest that an S-N bond between cysteine and S-mephenytoin is formed via an oxidative radical mechanism catalyzed by CYP2C19.