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Chin B Eap

Publications and source records attributed to Chin B Eap.

34 records · Page 2Linked to original sources
PubMed2004

CYP3A activity measured by the midazolam test is not related to 3435 C >T polymorphism in the multiple drug resistance transporter gene.

A recent study with 69 Japanese liver transplants treated with tacrolimus found that the MDR13435 C >T polymorphism, but not the MDR12677 G >T polymorphism, was associated with differences in the intestinal expression level of CYP3A4 mRNA. In the present study, over 6 h, we measured the kinetics of a 75 microg oral dose of midazolam, a CYP3A substrate, in 21 healthy subjects genotyped for the MDR13435 C >T and 2677 G >T polymorphism. No statistically significant differences were found in the calculated pharmacokinetic parameters between the three 3435 C >T genotypes (TT, CT and CC group, respectively: Cmax (mean +/- SD: 0.30 +/- 0.08 ng/ml, 0.31 +/- 0.09 ng/ml and 0.31 +/- 0.11 ng/ml; Apparent clearance: 122 +/- 29 l/h, 156 +/- 92 l/h and 111 +/- 35 l/h; t1/2: 1.9 +/- 1.1 h, 1.6 +/- 0.90 h and 1.7 +/- 0.7 h). In addition, the 30-min 1'OH midazolam to midazolam ratio, a marker of CYP3A activity, determined in 74 HIV-positive patients before the introduction of antiretroviral treatment, was not significantly different between the three 3435 C >T genotypes (mean ratio +/- SD: 3.65 +/- 2.24, 4.22 +/- 3.49 and 4.24 +/- 2.03, in the TT, CT and CC groups, respectively). Similarly, no association was found between the MDR12677 G >T polymorphism and CYP3A activity in the healthy subjects or in the HIV-positive patients. The existence of a strong association between the activity of CYP3A and MDR13435 C >T and 2677 G >T polymorphisms appears unlikely, at least in Caucasian populations and/or in the absence of specific environmental factors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene.

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.

Adult↗
PubMed2004

Stereoselective metabolism of citalopram in plasma and cerebrospinal fluid of depressive patients: relationship with 5-HIAA in CSF and clinical response.

Plasma and cerebrospinal fluid (CSF) concentrations of the enantiomers of citalopram (CIT), its N-demethylated metabolite demethylcitalopram (DCIT) and its deaminated metabolite citalopram propionic acid derivative (CIT-PROP) were measured in plasma and CSF in 22 depressed patients after a 4-week treatment with 40 mg/d citalopram, which was preceded by a 1-week washout period. CSF 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured at baseline and after the 4-week CIT medication period. Patients were assessed clinically, using the Hamilton Depression Rating Scale (21-item HAM-D): at baseline and then at weekly intervals. CSF concentrations of S-CIT and R-CIT were 10.6 +/- 4.3 and 20.9 +/- 6 ng/mL, respectively, and their CSF/plasma ratios were 52% +/- 9% and 48% +/- 6%, respectively. The CIT treatment resulted in a significant decrease (28%) of 5-HIAA (P < 0.0001) and a significant increase (41%) of HVA in the CSF. Multiple linear regression analyses were performed to identify the impact of plasma and CSF CIT enantiomers and its metabolites on CSF monoamine metabolites and clinical response. There were 10 responders as defined by a > or =50% decrease of the HAM-D score (DeltaHAM-D) after the 4-week treatment. DeltaHAM-D correlated (Spearman) significantly with CSF S-CIT (r = - 0.483, P < 0.05), CSF S-CIT-PROP (r = -0.543, P = 0.01) (a metabolite formed from CIT by monoamine oxidase [MAO]) and 5-HIAA decrease (Delta5-HIAA) (r = 0.572, P = 0.01). The demonstrated correlations between pharmacokinetic parameters and the clinical outcome as well as 5-HIAA changes indicate that monitoring of plasma S-CIT, CSF S-CIT and CSF S-CIT-PROP may be of clinical relevance.

Adult↗
PubMed2004

Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects.

The chiral antidepressant venlafaxine (VEN) is both a serotonin and a norepinephrine uptake inhibitor. CYP2D6 and CYP3A4 contribute to its metabolism, which has been shown to be stereoselective. Ten CYP2D6 genotyped and depressive (F32x and F33x, ICD-10) patients participated in an open study on the pharmacokinetic and pharmacodynamic consequences of a carbamazepine augmentation in VEN non-responders. After an initial 4-week treatment with VEN (195 +/- 52 mg/day), the only poor metabolizer out of 10 depressive patients had the highest plasma concentrations of S-VEN and R-VEN, respectively, whereas those of R-O-demethyl-VEN were lowest. Five non-responders completed the second 4-week study period, during which they were submitted to a combined VEN-carbamazepine treatment. In the only non-responder to this combined treatment, there was a dramatic decrease of both enantiomers of VEN, O-demethylvenlafaxine, N-desmethylvenlafaxine and N, O-didesmethylvenlafaxine in plasma, which suggests non-compliance, although metabolic induction by carbamazepine cannot entirely be excluded. The administration of carbamazepine [mean +/- SD, range: 360 +/- 89 (200-400) mg/day] over 4 weeks did not result in a significant modification of the plasma concentrations of the enantiomers of VEN and its O- and N-demethylated metabolites in the other patients. In conclusion, these preliminary observations suggest that the combination of VEN and carbamazepine represents an interesting augmentation strategy by its efficacy, tolerance and absence of pharmacokinetic modifications. However, these findings should be verified in a more comprehensive study.

Adolescent↗
PubMed2003

Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses.

We examined in vivo the influence of cytochrome P4503A4 (CYP3A4) activity, measured by the 30 min plasma 1'OH-midazolam/midazolam ratio after oral administration of 7.5 mg midazolam, on the methadone steady-state trough plasma concentrations in a group of 32 patients in methadone maintenance treatment. Patients were grouped as receiving 'low' (up to 99 mg/day, n = 10), 'high' (100-199 mg/day, n = 11) and 'very high' (> or = 200 mg/day, n = 11) doses of methadone, and the CYP3A4 metabolic activity was compared between the three groups. (S)-methadone and (R,S)-methadone, but not (R)-methadone, concentrations to dose ratios significantly correlated with the midazolam ratios (r(2) = -0.17, P = 0.018; r(2) = -0.14, P = 0.032; r(2) = -0.10, P = 0.083, respectively), with a 76% higher CYP3A4 activity in the very high-dose group as compared with the low-dose group. Significant differences in the CYP3A4 activity were calculated between the three groups (P = 0.0036), and group-to-group comparisons, using the Bonferroni correction, showed a significant difference between the low-dose and the very high-dose group (P = 0.0039), between the high-dose and the very high-dose group (P = 0.0064), but not between the low-dose and the high-dose group (P = 0.070). The higher CYP3A4 activity measured in patients receiving very high methadone doses could contribute to the need for higher doses in some patients, due to an increased metabolic clearance. This, however, must be confirmed by a prospective study.

Adult↗
PubMed2003

Identification of a novel splice-site mutation in the CYP1A2 gene.

AIMS: To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71-year-old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug. METHODS: The nucleotide sequence of the 7 exons, exon-intron boundaries and 5'-flanking region of the CYP1A2 gene was analysed by direct sequencing. RESULTS: Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians. CONCLUSIONS: This is the first report of a splice-site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.

Aged↗
PubMed2003

Routine therapeutic drug monitoring in patients treated with 10-360 mg/day citalopram.

From data collected during routine TDM, plasma concentrations of citalopram (CIT) and its metabolites demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were measured in 345 plasma samples collected in steady-state conditions. They were from 258 patients treated with usual doses (20-60 mg/d) and from patients medicated with 80-360 mg/d CIT. Most patients had one or several comedications, including other antidepressants, antipsychotics, lithium, anticonvulsants, psychostimulants and somatic medications. Dose-corrected CIT plasma concentrations (C/D ratio) were 2.51 +/- 2.25 ng mL-1 mg-1 (n = 258; mean +/- SD). Patients >65 years had significantly higher dose-corrected CIT plasma concentrations (n = 56; 3.08 +/- 1.35 ng mL-1 mg-1) than younger patients (n = 195; 2.35 +/- 2.46 ng mL-1 mg-1) (P = 0.03). CIT plasma concentrations in the generally recommended dose range were [mean +/- SD, (median)]: 57 +/- 64 (45) ng/mL (10-20 mg/d; n = 64), 117 +/- 95 (91) ng/mL (21-60 mg/d; n = 96). At higher than usual doses, the following concentrations of CIT were measured: 61-120 mg/d CIT, 211 +/- 103 (190) ng/mL (n = 93); 121-200 mg/d: 339 +/- 143 (322) ng/mL (n = 70); 201-280 mg/d: 700 +/- 408 (565) ng/mL (n = 18); 281-360 mg/d: 888 +/- 620 (616) ng/mL (n = 4). When only one sample per patient (at the highest daily dose if repeated dosages) is considered, there is a linear and significant correlation (n = 48, r = 0.730; P < 0.001) between daily dose (10-200 mg/d) and CIT plasma concentrations. In experiments with dogs, DDCIT was reported to affect the QT interval when present at concentrations >300 ng/mL. In this study, DDCIT concentration reached 100 ng/mL in a patient treated with 280 mg/d CIT. Twelve other patients treated with 140-320 mg/d CIT had plasma concentrations of DDCIT within the range 52-73 ng/mL. In a subgroup comprised of patients treated with > or =160 mg/d CIT and with CIT plasma concentrations < or =300 ng/mL, and patients treated with < or =200 mg/d CIT and CIT plasma concentrations > or = 600 ng/mL, the enantiomers of CIT and DCIT were also analyzed. The highest S-CIT concentration measured in this subgroup was 327 ng/mL in a patient treated with 140 mg/d CIT, but the highest S-CIT concentration (632 ng/mL) was measured in patient treated with 360 mg/d CIT. In conclusion, there is a highly linear correlation between CIT plasma concentrations and CIT doses, well above the usual dose range.

Adolescent↗
PubMed2003

Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans.

CYP2D6 is involved in the O-demethylation metabolic pathway of venlafaxine in humans. In this study, we investigated whether this isozyme is stereoselective. Plasma samples from seven CYP2D6 extensive metabolizers (EMs) and five CYP2D6 poor metabolizers (PMs), collected during a period without and with coadministration of quinidine, were analysed. Subjects were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulphate every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). The present results show that, although CYP2D6 catalyses the O-demethylation of both enantiomers of venlafaxine, it displays a marked stereoselectivity towards the (R)-enantiomer. The oral clearance of (R)-venlafaxine was found to be nine-fold higher in EMs compared to PMs [median (range) 173 (29-611) l/h versus 20 (16-24) l/h, P < 0.005], while it was two-fold higher for (S)-venlafaxine [73 (32-130) l/h versus 37 (21-44) l/h, P < 0.05]. In EMs, quinidine decreased (R)- and (S)-venlafaxine oral clearance by 12-fold ( 0.05) and four-fold ( 0.05), respectively. In contrast, quinidine did not have any effects on renal clearance of (R)-venlafaxine [4 (2-10) l/h for venlafaxine alone versus 5 (0.6-7) l/h for venlafaxine + quinidine] and of (S)-venlafaxine [4 (1-7) l/h for venlafaxine alone versus 3 (0.4-6) l/h for venlafaxine + quinidine]. The coadministration of quinidine to EMs resulted in an almost complete inhibition of the partial metabolic clearance of (R)-venlafaxine to O-demethylated metabolites [127 (10-493) l/h down to 1 (0.1-3) l/h, 0.05], while a seven-fold reduction was measured for (S)-venlafaxine [47 (14-94) l/h versus 7 (1-19) l/h, 0.05]. In PMs, coadministration of quinidine did not significantly change oral clearance and partial metabolic clearance of (R)- and (S)-venlafaxine to its various metabolites. In contrast, data obtained on the partial metabolic clearance of (R)- and (S)-venlafaxine to N-demethylated metabolites, a reaction which is mediated by CYP3A4, suggest a lack of stereoselectivity of this enzyme.

Administration, Oral↗
PubMed2002

Disposition of venlafaxine enantiomers in rats with hepatic encephalopathy after chronic drug treatment.

Portacaval shunted (PCS) rats, a model of hepatic encephalopathy, and control animals were administered racemic venlafaxine for 14 days (10 mg/kg). The levels of the S- and R-enantiomers and the S/R-enantiomer ratios of venlafaxine and its metabolites were assessed by an enantiomer-selective chromatographic assay in serum, brain parenchyma, and brain dialysate of both groups. Higher levels of the S- and R-enantiomers of venlafaxine were found in serum and brain of PCS vs. normal rats (median values of S- and R-venlafaxine in serum: 290 and 201 nM in PCS; 97 and 66 nM in normal rats; median values of S- and R-venlafaxine in cortex: 956 and 939 nM in PCS; 357 and 318 nM in normal rats). Interestingly, similar S/R-venlafaxine ratios were observed in PCS and normal rats both in serum (S/R = 1.4) and brain compartments (S/R = l.0-1.1). These findings may have clinical relevance for the safety of venlafaxine in chronic hepatic encephalopathy.

Animals↗
PubMed2002

Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study.

BACKGROUND: HIV-1-infected patients vary considerably by their response to antiretroviral treatment, drug concentrations in plasma, toxic events, and rate of immune recovery. This variability could have a genetic basis. We did a pharmacogenetics study to analyse the association between response to antiretroviral treatment and allelic variants of several genes. METHODS: In 123 patients, we did PCR analyses of the gene for the multidrug-resistance transporter (MDR1), which codes for P-glycoprotein, of genes coding for isoenzymes of cytochrome P450, CYP3A4, CYP3A5, CYP2D6, and CYP2C19, and of the gene for the chemokine receptor CCR5. We measured concentrations in plasma of the antiretroviral agents efavirenz and nelfinavir by high-performance liquid-chromatography, and measured levels of P-glycoprotein expression, CD4-cell count, and HIV-1 viraemia. FINDINGS: Median drug concentrations in patients with the MDR1 3435 TT, CT, and CC genotypes were at the 30th, 50th, and 75th percentiles, respectively (p=0.0001). In patients with CYP2D6 extensive-metaboliser or poor-metaboliser alleles, median drug concentrations were at percentiles 45 and 62.5, respectively (p=0.04). Patients with the MDR1 TT genotype 6 months after starting treatment had a greater rise in CD4-cell count (257 cells/microL) than patients with the CT (165 cells/microL) and CC (121 cells/microL) genotype (p=0.0048), and the best recovery of naïve CD4-cells. INTERPRETATION: The polymorphism MDR1 3435 C/T predicts immune recovery after initiation of antiretroviral treatment. This finding suggests that P-glycoprotein has an important role in admittance of antiretroviral drugs to restricted compartments in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Carbamazepine augmentation in depressive patients non-responding to citalopram: a pharmacokinetic and clinical pilot study.

Citalopram is a chiral antidepressant drug. Its eutomer, S-citalopram (escitalopram), has recently been introduced as an antidepressant. In an open pilot study, four outpatients and two inpatients with a major depressive episode (ICD-10), and who were nonresponders to a 4-week pretreatment with 40-60 mg/day citalopram, were comedicated for another 4-week period with carbamazepine (200-400 mg/day). Some of the patients suffered also from comorbidities: Phobic anxiety disorder with panic attacks (n=2), generalised anxiety disorder, alcohol abuse, dependent personality disorder, hypertension (n=1). After a 4-week augmentation therapy with carbamazepine, a significant (P<0.03) decrease of the plasma concentrations of S-citalopram and R-citalopram, by 27 and 31%, respectively, was observed. Apparently, the probable induction of CYP3A4 by carbamazepine results in a nonstereoselective increase in N-demethylation of citalopram. Moreover, there was a significant (P<0.03) decrease of the ratio S/R-citalopram propionic acid derivative, the formation of it being partly regulated by MAO-A and MAO-B. Already, within 1 week after addition of carbamazepine, there was a slight but significant (P<0.03) decrease of the MADRS depression scores, from 27.0+/-7.7 (mean+/-S.D.) to 23.3+/-6.6, and the final score on day 56 was 18.8+/-10.9. The treatment was generally well tolerated. There was no evidence of occurrence of a serotonin syndrome. After augmentation with carbamazepine, treatment related adverse events were: Nausea in one case, diarrhea in one case, and rash in two cases. In conclusion, the results of this pilot study suggest that carbamazepine augmentation of a citalopram treatment in previous nonresponders to citalopram may be clinically useful, but that in addition carbamazepine can lead to a decrease of the plasma concentrations of the active enantiomer escitalopram.

Adult↗
PubMed2002

Enantiomers' potential in psychopharmacology--a critical analysis with special emphasis on the antidepressant escitalopram.

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form-thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer-escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram-appears to be fulfilling its preclinical promise in the clinic.

Animals↗
PubMed2002

Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers.

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.

Adult↗
PubMed2002

Very long half-life of paroxetine following intoxication in an extensive cytochrome P4502D6 metabolizer.

A very long half-life of paroxetine (195 h instead of the usual value of around 16 h) was measured after an overdose with 2 g paroxetine and 1 g clorazepate in a patient who was an extensive cytochrome P4502D6 metabolizer. The patient recovered well without any clinically significant complications. A consequence of the close monitoring of paroxetine levels in this patient was that it was decided not to reintroduce any other antidepressant despite her suicide attempt, until normal levels of paroxetine had been reached, which took over 1 month.

Anti-Anxiety Agents↗
PubMed2002

Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence.

Methadone is widely used for the treatment of opioid dependence. Although in most countries the drug is administered as a racemic mixture of (R)- and (S)- methadone, (R)-methadone accounts for most, if not all, of the opioid effects. Methadone can be detected in the blood 15-45 minutes after oral administration, with peak plasma concentration at 2.5-4 hours. Methadone has a mean bioavailability of around 75% (range 36-100%). Methadone is highly bound to plasma proteins, in particular to alpha(1)-acid glycoprotein. Its mean free fraction is around 13%, with a 4-fold interindividual variation. Its volume of distribution is about 4 L/kg (range 2-13 L/kg). The elimination of methadone is mediated by biotransformation, followed by renal and faecal excretion. Total body clearance is about 0.095 L/min, with wide interindividual variation (range 0.02-2 L/min). Plasma concentrations of methadone decrease in a biexponential manner, with a mean value of around 22 hours (range 5-130 hours) for elimination half-life. For the active (R)-enantiomer, mean values of around 40 hours have been determined. Cytochrome P450 (CYP) 3A4 and to a lesser extent 2D6 are probably the main isoforms involved in methadone metabolism. Rifampicin (rifampin), phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz decrease methadone blood concentrations, probably by induction of CYP3A4 activity, which can result in severe withdrawal symptoms. Inhibitors of CYP3A4, such as fluconazole, and of CYP2D6, such as paroxetine, increase methadone blood concentrations. There is an up to 17-fold interindividual variation of methadone blood concentration for a given dosage, and interindividual variability of CYP enzymes accounts for a large part of this variation. Since methadone probably also displays large interindividual variability in its pharmacodynamics, methadone treatment must be individually adapted to each patient. Because of the high morbidity and mortality associated with opioid dependence, it is of major importance that methadone is used at an effective dosage in maintenance treatment: at least 60 mg/day, but typically 80-100 mg/day. Recent studies also show that a subset of patients might benefit from methadone dosages larger than 100 mg/day, many of them because of high clearance. In clinical management, medical evaluation of objective signs and subjective symptoms is sufficient for dosage titration in most patients. However, therapeutic drug monitoring can be useful in particular situations. In the case of non-response trough plasma concentrations of 400 microg/L for (R,S)-methadone or 250 microg/L for (R)-methadone might be used as target values.

Cytochrome P-450 Enzyme System↗