Erik Skjelbo

Fluvoxamine is a potent inhibitor of cytochrome P4501A2

Fluvoxamine is a new antidepressant and selectively inhibits serotonin reuptake (SSRI). The present study demonstrates that fluvoxamine is a very potent inhibitor of the high-affinity O-deethylation of phenacetin, which is catalysed by cytochrome P4501A2 (CYP1A2), in microsomes from three human livers. Thus, the apparent inhibitor constant of fluvoxamine, Ki, ranged from 0.12 to 0.24 microM. Seven other SSRIs, citalopram, N-desmethylcitalopram, fluoxetine, norfluoxetine, paroxetine, sertraline and litoxetin either did not inhibit or were weak inhibitors of the O-deethylation of phenacetin. Our findings explain the mechanism of the pharmacokinetic interactions between fluvoxamine and drugs that are metabolized by CYP1A2, e.g. theophylline and imipramine.

The relationship between paroxetine and the sparteine oxidation polymorphism

The relationship between the selective serotonin reuptake inhibitor paroxetine and the sparteine oxidation polymorphism was investigated in a combined single‐dose (30 mg) and steady‐state (30 mg/day for 2 weeks) study including a panel of nine extensive metabolizers and eight poor metabolizers of sparteine. The median area under the plasma concentration‐time curve (AUC) after the first paroxetine dose was about seven times higher in poor metabolizers than in extensive metabolizers (3910 versus 550 nmol · hr/L), whereas at steady state the median AUCsst interphenotype difference was only twofold (4410 versus 2550 nmol · hr/L). Plasma half‐life and steady‐state plasma concentration were significantly longer and higher, respectively, in poor metabolizers than in extensive metabolizers (41 versus 16 hours and 151 versus 81 nmol/L). Paroxetine pharmacokinetics were linear in poor metabolizers and nonlinear only in extensive metabolizers. Sparteine metabolic ratio (MR = 12 hour urinary ratio of sparteine/de‐hydrosparteine), increased during treatment with paroxetine in subjects who were extensive metabolizers, and after 14 days treatment two extensive metabolizers were phenotyped as poor metabolizers and the remaining extensive metabolizers were changed into extremely slow extensive metabolizers with sparteine MRs of 5.7 to 16.5. The inhibition of sparteine metabolism was rapidly reversed after cessation of paroxetine administration. In the poor metabolizers there were no significant changes in MRs during the study. It is concluded that paroxetine and sparteine metabolism cosegregates, but the interphenotype difference in metabolism was less prominent at steady state than after a single dose, presumably because of saturation of the sparteine oxygenase (CYP2D6) in subjects who were extensive metabolizers. Paroxetine is a potent inhibitor of sparteine oxidation by CYP2D6 in vivo.

The mephenytoin oxidation polymorphism is partially responsible for the N‐demethylation of imipramine

The metabolism of imipramine in six poor metabolizers of mephenytoin was compared with the metabolism of 16 extensive metabolizers of mephenytoin from an earlier study. Each subject was given single doses of 100 mg imipramine hydrochloride and 100 mg desipramine hydrochloride on separate occasions. Imipramine demethylation clearance was 0.74 L · min−1 (mean; range, 0.31–1.24) in poor metabolizers of mephenytoin compared with 1.43 L · min−1 (mean; range, 0.61–3.81) in extensive metabolizers of mephenytoin (p = 0.01, Mann‐Whitney U test). It has previously been shown that the imipramine clearance by way of other pathways and desipramine oral clearance, both largely representing 2‐hydroxylation, are considerably lower in poor metabolizers of sparteine than in extensive metabolizers of sparteine. In contrast, five subjects who were poor metabolizers of mephenytoin and extensive metabolizers of sparteine and a control group of 11 subjects who were extensive metabolizers of mephenytoin and sparteine showed no statistically significant difference with regard to these parameters. One subject who was a poor metabolizer of mephenytoin and sparteine had the lowest imipramine oral clearance of all 22 subjects studied. In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2‐hydroxylation by way of the sparteine oxygenase (P450IID6) and demethylation by way of the mephenytoin oxygenase (P450IIC8).

Chloroguanide metabolism in relation to the efficacy in malaria prophylaxis and the S‐mephenytoin oxidation in Tanzanians

S‐Mephenytoin and chloroguanide (proguanil) oxidation was studied in 216 Tanzanians. The mephenytoin S/R ratio in urine ranged from <0.1 to 1.16. The distribution was skewed to the right, without evidence of a bimodal distribution. Ten subjects (4.6%, 2.2% to 8.3%, 95% CI) with an S/R mephenytoin ratio >0.9, were arbitrarily defined as poor metabolizers of mephenytoin. The chloroguanide/cycloguanil ratio ranged from 0.82 to 249. There was a significant correlation between the mephenytoin S/R ratio and the chloroguanide/cycloguanil ratios (rs = 0.73; p < 0.00001). This indicates that cytochrome P4502C19 or CYP2C19 is a major enzyme that catalyzes the bioactivation of chloroguanide to cycloguanil. Chloroguanide is a pro‐drug, and hence a low CYP2C19 activity may lead to prophylactic failure caused by inadequate formation of cycloguanil. Fifty‐eight women who previously took either 200 mg chloroguanide daily (n = 26) or 200 mg chloroguanide daily plus 300 mg chloroquine weekly (n = 32) in a malaria chemoprophylaxis study showed that there was a significant correlation between the number of earlier breakthrough parasitemia episodes and the chloroguanide/cycloguanil ratio (rs = 0.30; p = 0.02). The breakthrough rate did not correlate with the S/R mephenytoin ratio. However, other factors, such as exposure to mosquitoes and sensitivity of the plasmodium to cycloguanil, are probably more important.

Role of Genetic Polymorphism in Psychopharmacology — An Update

Pharmacogenetics is concerned with the genetic basis for interindividual differences in the clinical reponse to drugs. The study of genetic polymorphism in drug metabolism has been an area of particular interest. A genetic polymorphism is a monogenic or mendelian trait that exists in the population in at least two phenotypes (and presumably in at least two genotypes), the rarest of whom exists in at least 1%–2% (Vogel and Motulsky 1982). Thus, two phenotypes are discernible in the case of genetic polymorphism in drug metabolism: a slowly metabolizing phenotype who may develop toxic plasma (tissue) concentrations when a standard dose regimen is employed and a rapidly metabolizing phenotype who may develop subtherapeutic concentrations.

Hyponatraemia in very old nonhospitalised people: association with drug use.

AbstractObjective: Hyponatraemia is one of the major problems in geriatric inpatients. However, in nonhospitalised elderly, the preponderance of hyponatraemia and the importance of the effect of drug intake on serum sodium concentrations are little known. This study investigated the prevalence of hyponatraemia in very old nonhospitalised people, controlling for factors that may induce hyponatraemia (especially drug use). Methods: Data on serum sodium concentration, health and drug use were retrieved for 185 persons aged 92 to 93 years (the 1905 cohort) and 147 persons aged 100 years (the centenarian cohort) participating in two major population-based studies of elderly people in Denmark. Data were analysed by comparing median serum sodium concentrations between users and nonusers of various drugs after controlling for the influence of age, sex, cancer, heart failure, hypothyroidism, renal failure and smoking. Furthermore, the preponderance of drug use in the patients with clinically relevant hyponatraemia was compared with that in persons with normal serum sodium concentrations. Results: Median serum sodium concentration was 140 mmol/L for the centenarians and 141 mmol/L for the 1905 cohort. In total, 19 persons had hyponatraemia (serum sodium concentration ≤134 mmol/L). There was no association between median serum sodium concentration and any of the above-mentioned diseases, or sex or smoking. Of the drugs generally known to cause hyponatraemia, only omeprazole and oral antidiabetic agents were associated with significantly lower median serum sodium concentrations (difference 3 mmol/L). Use of thiazide diuretics was significantly more common than expected in persons with hyponatraemia compared with persons with a normal serum sodium concentration (7 of 19 vs 46 of 270 individuals). Furthermore, the results suggested that digoxin and lactulose might be associated with a lowered median serum sodium concentration. Conclusion: This study demonstrates that severe hyponatraemia was rarely seen in a population-based sample of very old persons and that drugs have only a limited influence on serum sodium concentration. The only drug class associated with clinically relevant hyponatraemia was thiazide diuretics, which were used by significantly more persons with hyponatraemia. Furthermore, this study suggests that digoxin and lactulose use is associated with lower serum sodium concentrations in the elderly.

Imipramine: a model drug for P450 research.

Publisher Summary This chapter focuses on a model drug for P450 research, that is, imipramine. Imipramine is the prototype of the class of tricyclic antidepressants. The drug is eliminated by oxidation catalyzed by the cytochrome P450 system in the liver. The major oxidative pathways are N-demethylation in the side chain to the active metabolite desipramine and aromatic hydroxylation to 2-hydroxyimipramine. Desipramine is eliminated by 2-hydroxylation and by further N-demethylation to didesmethylimipramine and by 10-hydroxylation. With the development of an applicable thin-layer chromatography (TLC) method for the quantitative assessment of imipramine and desipramine in plasma it became possible to establish the basic pharmacokinetics of imipramine. The microsomal HPLC method was developed to use the 2-hydroxylation of imipramine as a marker reaction for CYP2D6 in vitro. The chapter gives an account of the high-performance liquid chromatography (HPLC) methods used for the assay of imipramine and its metabolites in plasma, urine, and human liver microsome preparations.

Risk factors in elderly taking psychotropic drugs: Significance of genetic polymorphism in drug oxidation

The pattern of adverse drug reactions in elderly is both quantitatively and qualitatively different from that in younger patients. This relates to age-associated changes in physiology, pharmacodynamics and pharmacokinetics. The combination of several risk factors including the use of several drugs concurrently is of special importance in the elderly. Extreme pharmacokinetic variations due to genetic polymorphism in drug action, may, although not in itself age-related, cause particular problems in the elderly. The best-studied drug oxidation polymorphism, related to the model substances sparteine and debrisoquine, is important for several types of drugs, including tricyclic antidepressants, several neuroleptics and several other types of drugs. Sparteine/debrisoquine-poor metabolizers will with standard doses of tricyclic antidepressants or neuroleptics develop very high steady-state blood levels, and this may cause particular problems in the elderly. There are several examples of how the genetic polymorph...