Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00528 (Monit)
 35,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver metabolism may be modified after liver transplantation according to the phenotype of the donor and may be influenced by posttransplantation complications. The CYP2D6 phenotype was assessed in 13 patients (group I) before and after liver transplantation using debrisoquine. CYP2D6 activity was also assessed in vitro on microsomes from the liver of the recipients and the donors, using dextromethorphan. Twelve patients were extensive metabolizers both before and after transplantation. One apparently poor metabolizer was transplanted with the liver of another poor metabolizer. The intrinsic clearance of dextromethorphan (CL(int)) measured on recipient liver microsomes was significantly lower than that on donor liver microsomes (p < 0.05). In extensive metabolizers, the debrisoquine metabolic ratio was correlated with CL(int) before (r = 0.78, p < 0.05) and after (r = 0.89, p < 0.0005) transplantation. Debrisoquine phenotype was measured repeatedly in nine additional patients (group II) up to 3 years after liver transplantation. Their phenotype was stable during the follow-up observation, although the variations observed may be clinically relevant. Therefore, no change in CYP2D6 phenotype (extensive/poor metabolizer) was observed because of the liver transplantation, and the debrisoquine log metabolic ratio was largely unaffected by the liver complications observed during the posttransplantation follow-up observation.
Ther Drug Monit 1995 Apr
PMID:Stability of debrisoquine (CYP2D6) phenotype in liver transplant patients. 762 97

Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean C/D of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio C/D in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio C/D was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.
Ther Drug Monit 1994 Feb
PMID:The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline. 790 76

Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.
Ther Drug Monit 1994 Aug
PMID:Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. 797 26

The effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine caused a significant prolongation of imipramine half-life (from 22.8 +/- 6.4 to 40.5 +/- 5.0 h, means +/- SD, p < 0.01) and a marked decrease in imipramine apparent oral clearance (from 1.02 +/- 0.19 to 0.28 +/- 0.06 L/h/kg, p < 0.0001). No significant changes in desipramine kinetics were observed during fluvoxamine treatment. These findings indicate that, at the dosage tested, fluvoxamine markedly inhibits the demethylation of imipramine without affecting significantly the CYP2D6-mediated hydroxylation of desipramine.
Ther Drug Monit 1993 Jun
PMID:Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects. 833 5

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
Ther Drug Monit 1993 Feb
PMID:Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms. 845 74

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
Ther Drug Monit 1993 Feb
PMID:Citalopram: interaction studies with levomepromazine, imipramine, and lithium. 845 75

An automated column-switching technique coupled to isocratic high-performance liquid chromatography (HPLC) with fluorescence detection was developed for simultaneous determination of dextromethorphan and its three major metabolites, dextrorphan, hydroxymorphinan, and methoxymorphinan. After cleavage of conjugates by incubation with glucuronidasearylsulfatase at 37 degrees C for 15 h, plasma samples were injected directly into the HPLC system. Dextromethorphan and metabolites were retained on a cleanup column (10 x 4.6 mm internal diameter [ID]) filled with cyanopropyl (CN) material (Hypersil CPS, 10-microns article size) while interfering proteins and lipids were washed to waste. After column switching, the drugs were eluted from the cleanup column and separated on Spherisorb CN material (5-microns particle size, column size 250 x 4.6 mm ID). Fluorescence detection was carried out with an excitation wavelength of 220 nm and an emission wavelength of 305 nm. Sample cleanup and HPLC separation were completed within 20 min. Regression analyses found linearity (r > 0.99) between drug concentration and detector response over a wide range-5-220 ng/ml for dextromethorphan, 5-550 ng/ml for dextrorphan, 5-500 ng/ml for hydroxymorphinan, and 5-200 ng/ml for methoxymorphinan. The limit of quantification was approximately 5 ng/ml, and the recovery was > 90% for all compounds. At concentrations of 20-500 ng/ml, the intra- and interassay coefficients of variation ranged from 3.5 to 14.6% and from 7.0 to 14.0%, respectively. The method is suitable for in vivo phenotyping of CYP2D6 activity, which catalyzes the O-demethylation of dextromethorphan to dextrorphan, and is also applicable to pharmacokinetic studies in man.
Ther Drug Monit 1996 Jun
PMID:Automated determination of dextromethorphan and its main metabolites in human plasma by high-performance liquid chromatography and column switching. 873 72

The kinetics of a single oral dose of desipramine (DMI; 100 mg) were studied in eight epileptic patients chronically treated with phenobarbital (PB) and in eight drug-free healthy controls. All subjects were extensive metabolizers with respect to the genetically determined CYP2D6-related metabolic polymorphism. Compared with controls, epileptic patients exhibited lower peak plasma DMI concentrations (74 +/- 24 vs. 107 +/- 32 nmol/L; means +/- SD, p < 0.05), smaller DMI area-under-the-curve values (1,943 +/- 461 vs. 3,234 +/- 1,145 nmol L-1 h; p < 0.01), and shorter DMI elimination half-lives (15.1 +/- 2.1 vs. 20.6 +/- 3.4 h; p < 0.01). The proportion of the dose excreted as 2-hydroxydesipramine (2-OH-DMI) was significantly higher in the patients (54 +/- 8 vs. 40 +/- 9%; p < 0.05). In one single poor metabolizer volunteer, a 3-week treatment with PB was associated with no major changes in DMI kinetics, but the urinary excretion of 2-OH-DMI tended to increase. These results suggest that PB is an inducer of the 2-hydroxylation of DMI, a reaction primarily catalyzed by CYP2D6, but do not provide further information on the specific P450 isoenzyme(s) being induced.
Ther Drug Monit 1996 Feb
PMID:Phenobarbital induces the 2-hydroxylation of desipramine. 884 23

The multiplicity of the drug-metabolizing cytochrome P450 system was discovered 20 years ago. During the past 10 years the complementary DNAs of the most important P450 enzymes have been cloned and sequenced, and much has been learned about their substrate specificities, selective inhibitors, and functional characteristics. Cytochrome P4501A2 (CYP1A2), CYP2C19, CYP2D6, and CYP3A4 are the most important P450s catalyzing the biotransformation of psychotropic drugs. Assessment of the activity of individual P450 enzymes makes it possible to forecast an appropriate initial dose in a patient. At present, this strategy can be recommended only for CYP2D6 before treatment with tricyclic antidepressants and certain neuroleptics. Important drug-drug interactions can be predicted if two substrates or a substrate and an inhibitor of a particular P450 are co-administered. Therapeutic drug monitoring is of invaluable help in discovering and handling this type of interaction.
Ther Drug Monit 1996 Aug
PMID:Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry. 885 57

A case is presented in which toxic concentrations of imipramine (Tofranil) resulted from the co-administration of low-dose thioridazine (Mellaril). This probably occurred in an individual with genetically reduced capacity for oxidative drug metabolism, specifically via thioridazine's interference with the hepatic cytochrome P450IID6 isoenzyme (CYP2D6). In addition, coelution of thioridazine and its metabolites resulted in false elevations of imipramine and desipramine as measured by a common high-performance liquid chromatography (HPLC) method (cyanopropyl column). In contrast, an enzyme immunoassay (Abbott TDxFLx) and a second reference HPLC method (silica column) accurately resolved the analytes. This combination of psychiatric drugs is not uncommon in the pediatric population and is one of which both clinicians and laboratorians need to be aware. To the author's knowledge, this is the first report of interferences of thioridazine with both the metabolism and measurement of imipramine in a pediatric patient.
Ther Drug Monit 1996 Dec
PMID:Thioridazine interferences with imipramine metabolism and measurement. 894 74


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