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Biomedical subjects

Chin B Eap

Publications and source records attributed to Chin B Eap.

At least 19 recordsLinked to original sources
PubMed2006

Orosomucoid (alpha1-acid glycoprotein) plasma concentration and genetic variants: effects on human immunodeficiency virus protease inhibitor clearance and cellular accumulation.

BACKGROUND AND OBJECTIVE: Protease inhibitors are highly bound to orosomucoid (ORM) (alpha1-acid glycoprotein), an acute-phase plasma protein encoded by 2 polymorphic genes, which may modulate their disposition. Our objective was to determine the influence of ORM concentration and phenotype on indinavir, lopinavir, and nelfinavir apparent clearance (CL(app)) and cellular accumulation. Efavirenz, mainly bound to albumin, was included as a control drug. METHODS: Plasma and cells samples were collected from 434 human immunodeficiency virus-infected patients. Total plasma and cellular drug concentrations and ORM concentrations and phenotypes were determined. RESULTS: Indinavir CL(app) was strongly influenced by ORM concentration (n = 36) (r2 = 0.47 [P = .00004]), particularly in the presence of ritonavir (r2 = 0.54 [P = .004]). Lopinavir CL(app) was weakly influenced by ORM concentration (n = 81) (r2 = 0.18 [P = .0001]). For both drugs, the ORM1 S variant concentration mainly explained this influence (r2 = 0.55 [P = .00004] and r2 = 0.23 [P = .0002], respectively). Indinavir CL(app) was significantly higher in F1F1 individuals than in F1S and SS patients (41.3, 23.4, and 10.3 L/h [P = .0004] without ritonavir and 21.1, 13.2, and 10.1 L/h [P = .05] with ritonavir, respectively). Lopinavir cellular exposure was not influenced by ORM abundance and phenotype. Finally, ORM concentration or phenotype did not influence nelfinavir (n = 153) or efavirenz (n = 198) pharmacokinetics. CONCLUSION: ORM concentration and phenotype modulate indinavir pharmacokinetics and, to a lesser extent, lopinavir pharmacokinetics but without influencing their cellular exposure. This confounding influence of ORM should be taken into account for appropriate interpretation of therapeutic drug monitoring results. Further studies are needed to investigate whether the measure of unbound drug plasma concentration gives more meaningful information than total drug concentration for indinavir and lopinavir.

Adult↗
PubMed2006

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2006

Association of CYP3A5 genotypes with blood pressure and renal function in African families.

OBJECTIVE: Renal cytochrome P450 3A5 (CYP3A5) activity has been associated with blood pressure and salt sensitivity in humans. We determined whether CYP3A5 polymorphisms are associated with ambulatory blood pressure (ABP) and with glomerular filtration rate (GFR) in African families. METHODS: Using a cross-sectional design, 375 individuals from 72 families, each with at least two hypertensive siblings, were recruited through a hypertension register in the Seychelles (Indian Ocean). We analyzed the association between the CYP3A5 alleles (*1, *3, *6 and *7) and ABP, GFR and renal sodium handling (fractional excretion of lithium), from pedigree data, allowing for other covariates and familial correlations. RESULTS: CYP3A5*1 carriers increased their daytime systolic and diastolic ABP with age (0.55 and 0.23 mmHg/year) more than non-carriers (0.21 and 0.04 mmHg/year). CYP3A5*1 had a significant main effect on daytime systolic/diastolic ABP [regression coefficient (SE): -29.6 (10.0)/-8.2 (4.1) mmHg, P = 0.003/0.045, respectively] and this effect was modified by age (CYP3A5*1 x age interactions, P = 0.017/0.018). For night-time ABP, the effect of CYP3A5*1 was modified by urinary sodium excretion, not by age. For renal function, CYP3A5*1 carriers had a 7.6(3.8) ml/min lower GFR (P = 0.045) than non-carriers. Proximal sodium reabsorption decreased with age in non-carriers, but not in CYP3A5*1 carriers (P for interaction = 0.02). CONCLUSIONS: These data demonstrate that CYP3A5 polymorphisms are associated with ambulatory BP, CYP3A5*1 carriers showing a higher age- and sodium- related increase in ABP than non-carriers. The age effect may be due, in part, to the action of CYP3A5 on renal sodium handling.

Adult↗
PubMed2006

Risperidone-induced symptomatic hyperprolactinaemia in adolescents.

Studies performed in adult patients unambiguously demonstrate a marked effect of risperidone on prolactin blood levels, with possible clinical effects related to hyperprolactinemia, such as gynecomastia and galactorrhea. However, the largest study performed in children and adolescents showed a weak effect of risperidone on prolactin concentrations during short-term treatment and a negligible effect during long-term treatment, which was probably because of the relatively low dosages of risperidone used [approximately 0.04 mg/(kg x d)]. Among the 10 psychotic adolescents treated with risperidone in our unit, we had 3 cases of gynecomastia in 3 male patients and 2 cases of galactorrhea in 2 female patients. The prolactin blood levels in these cases and in 3 other patients without apparent prolactin-related side effects were all above the normal range (median, 59 ng/mL; range, 30-123 ng/mL). Thus, risperidone administered to adolescents at doses commonly used for the treatment of psychotic symptoms can strongly increase prolactin levels, with clinical consequences such as gynecomastia and/or galactorrhea. Given that the long-term effects of antipsychotic drug-induced hyperprolactinemia are not well documented, especially regarding osteopenia, infertility, growth, and pubertal delay, risperidone should be administered with caution to children and adolescents.

Adolescent↗
PubMed2006

Aripiprazole and suicidality.

Cases of psychotic symptoms that worsen after treatment with aripiprazole have been described. We report the case of a 19-year-old patient who, although her psychotic symptoms did not worsen, attempted suicide after switching from risperidone to aripiprazole. The patient had not shown any aggressive behaviour towards herself or others in the 18 months before the introduction of aripiprazole, nor following its discontinuation (12 months). The observed time sequence, with the repetition 4 weeks later of high suicidal behaviour, led us to consider that this effect might possibly be linked to the aripiprazole treatment, which could have increased the risk of suicide in this patient.

Adult↗
PubMed2006

Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Long-term citalopram administration reduces responsiveness of HPA axis in patients with major depression: relationship with S-citalopram concentrations in plasma and cerebrospinal fluid (CSF) and clinical response.

RATIONALE: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a well-documented neurobiological finding in major depression. Moreover, clinically effective therapy with antidepressant drugs may normalize the HPA axis activity. OBJECTIVE: The aim of this study was to test whether citalopram (R/S-CIT) affects the function of the HPA axis in patients with major depression (DSM IV). METHODS: Twenty depressed patients (11 women and 9 men) were challenged with a combined dexamethasone (DEX) suppression and corticotropin-releasing hormone (CRH) stimulation test (DEX/CRH test) following a placebo week and after 2, 4, and 16 weeks of 40 mg/day R/S-CIT treatment. RESULTS: The results show a time-dependent reduction of adrenocorticotrophic hormone (ACTH) and cortisol response during the DEX/CRH test both in treatment responders and nonresponders within 16 weeks. There was a significant relationship between post-DEX baseline cortisol levels (measured before administration of CRH) and severity of depression at pretreatment baseline. Multiple linear regression analyses were performed to identify the impact of psychopathology and hormonal stress responsiveness and R/S-CIT concentrations in plasma and cerebrospinal fluid (CSF). The magnitude of decrease in cortisol responsivity from pretreatment baseline to week 4 on drug [delta-area under the curve (AUC) cortisol] was a significant predictor (p<0.0001) of the degree of symptom improvement following 16 weeks on drug (i.e., decrease in HAM-D21 total score). The model demonstrated that the interaction of CSF S-CIT concentrations and clinical improvement was the most powerful predictor of AUC cortisol responsiveness. CONCLUSION: The present study shows that decreased AUC cortisol was highly associated with S-CIT concentrations in plasma and CSF. Therefore, our data suggest that the CSF or plasma S-CIT concentrations rather than the R/S-CIT dose should be considered as an indicator of the selective serotonergic reuptake inhibitors (SSRIs) effect on HPA axis responsiveness as measured by AUC cortisol response.

Adrenocorticotropic Hormone↗
PubMed2005

Prevalence of substance use in a Swiss psychiatric hospital: interview reports and urine screening.

BACKGROUND: Co-morbid substance misuse is common in psychiatric disorders, has potentially severe adverse consequences and may be frequently undetected. AIMS: To measure the prevalence of substance use among patients admitted to a Swiss psychiatric hospital and to examine the potential utility of routine urine drug screening in this setting. METHOD: 266 inpatients were included. 238 patients completed the interview and 240 underwent a urine drug screening. RESULTS: Lifetime prevalence of substance use among psychiatric patients was very high for alcohol (98%; 95% CI: 96-100), benzodiazepines (86%; 95% CI: 82-91) and cannabis (53%; 95% CI: 47-60), but also for "hard drugs" like cocaine (25% ; 95% CI: 19-30) or opiates (20%; 95% CI: 15-25). Regular current use of alcohol (32%; 95% CI: 26-38) or cannabis (17%; 95% CI: 12-22) was the most frequent. Substance use was associated with male sex, younger age, unmarried status and nicotine smoking. Urine screening confirms reports from patients on recent use, and remained positive for cannabis during hospitalisation, but not for cocaine nor for opiates. CONCLUSION: Substance use is frequent among psychiatric patients. Systematic interviewing of patients about their substance use remains essential, and is usually confirmed by urine screening. Urine screening can be useful to provide specific answers about recent use.

Adolescent↗
PubMed2005

Neuropeptide Y and corticotropin-releasing hormone in CSF mark response to antidepressive treatment with citalopram.

Neuropeptides appear to play a role in the pathophysiology of depression and electroconvulsive treatment and lithium affect these compounds in human cerebrospinal fluid (CSF) and rodent brain. Consequently, we investigated whether long-term treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram (Cit) would also affect neuropeptides in CSF of depressed patients. Changes in CSF monoamine metabolites were also explored. CSF concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity (-LI), neuropeptide Y (NPY)-LI, and Cit were determined in 21 patients with major depression. Lumbar puncture was performed in the morning at baseline and was repeated after at least 4 wk of Cit treatment (40 mg/d). The severity of depression was assessed by the Hamilton Rating Scale for Depression (HAMD). Cit treatment was associated with a significant increase in NPY-LI and decrease in CRH-LI. An evaluation of the relationship between changes in concentrations of NPY-LI, CRH-LI, and the clinical response showed significant correlations between these parameters. Significant NPY and CRH changes in CSF following treatment as well as correlations to changes in HAMD support the hypothesis that these two peptides play a role in affective disorders and are markers of therapeutic response.

Adult↗
PubMed2005

Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients.

OBJECTIVE: To measure the in vivo variations of CYP3A activity induced by anti-HIV drugs in human immunodeficiency virus (HIV)1-positive patients. METHODS: A low oral dose of midazolam (MID) (0.075 mg) was given to the patients and the 30-min total 1-OH midazolam (1-OHMID)/MID ratio was determined. Patients were phenotyped either before the introduction of antiretroviral treatments (control group, 90 patients) or after a variable period of antiretroviral treatment (56 patients). Twenty-one subjects underwent multiple phenotyping tests (before and during the course of the treatment). RESULTS: The median MID ratio was 3.51 in the control group (range 0.20-14.6). It was 5-fold higher in the group with efavirenz (28 patients; median, range: 16.0, 3.81-367; P < 0.0001), 13-fold lower with nelfinavir (18 patients; 0.27, 0.06-36.3; P < 0.0001), 17-fold lower with efavirenz + ritonavir (three patients; 0.21, 0.05-0.47; P = 0.006), 50-fold lower with ritonavir (four patients; 0.07, 0.06-0.17; P = 0.0007), and 7-fold lower with nevirapine + (ritonavir or nelfinavir or grapefruit juice) (three patients; 0.48, 0.03-1.83; P = 0.03). CYP3A activity was lower in the efavirenz + ritonavir group (P = 0.01) and in the ritonavir group (P = 0.04) than in the nelfinavir group, although already strongly inhibited in the latter. CONCLUSION: The low-dose MID phenotyping test was successfully used to measure the in vivo variations of CYP3A activity induced by antiretroviral drugs. Efavirenz strongly induces CYP3A activity, while ritonavir almost completely inhibits it. Nelfinavir strongly decreases CYP3A activity, but to a lesser extent than ritonavir. The inhibition of CYP3A by ritonavir or nelfinavir offsets the inductive effects of efavirenz or nevirapine administered concomitantly. Finally, no induction of CYP3A activity was noticeable after long-term administration of ritonavir at low dosages (200 mg/day b.i.d.) or of nelfinavir at standard dosages (2,500 mg/day b.i.d.).

Adult↗
PubMed2005

Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment.

BACKGROUND AND OBJECTIVE: Recent in vitro studies have suggested an important role of cytochrome P450 (CYP) 2B6 and CYP2C19 in methadone metabolism. We aimed to determine the influence of CYP2B6, CYP2C9, and CYP2C19 genetic polymorphism on methadone pharmacokinetics and on the response to treatment. METHODS: We included 209 patients in methadone maintenance treatment on the basis of their response to treatment and their daily methadone dose. Patients were genotyped for CYP2B6, CYP2C9, and CYP2C19. Steady-state trough and peak (R)-, (S)-, and (R,S)-plasma levels and peak-to-trough plasma level ratios were measured. RESULTS: CYP2B6 genotype influences (S)-methadone and, to a lesser extent, (R)-methadone plasma levels, with the median trough (S)-methadone plasma levels being 105, 122, and 209 ng . kg/mL . mg for the noncarriers of allele *6, heterozygous carriers, and homozygous carriers (*6/*6), respectively (P = .0004). CYP2C9 and CYP2C19 genotypes do not influence methadone plasma levels. Lower peak and trough plasma levels of methadone and higher peak-to-trough ratios were measured in patients considered as nonresponders [median (R,S)-methadone trough plasma levels of 183 and 249 ng . kg/mL . mg (P = .0004) and median peak-to-trough ratios of 1.82 and 1.58 for high-dose nonresponders and high-dose responders, respectively (P = .0003)]. CONCLUSION: Although CYP2B6 influences (S)-methadone plasma levels, given that only (R)-methadone contributes to the opioid effect of this drug, a major influence of CYP2B6 genotype on response to treatment is unlikely and has not been shown in this study. Lower plasma levels of methadone in nonresponders, suggesting a higher clearance, and higher peak-to-trough ratios, suggesting a shorter elimination half-life, are in agreement with the usual clinical measures taken for such patients, which are to increase methadone dosages and to split the daily dose into several intakes.

Adult↗
PubMed2005

Effect of age and gender on citalopram and desmethylcitalopram steady-state plasma concentrations in adults and elderly depressed patients.

The effect of aging on steady-state plasma concentrations of citalopram (CIT) and desmethylcitalopram (DCIT) was investigated in 128 depressive patients treated with 10-80 mg/day CIT. They were separated into three groups, with age up to 64 years (mean age+/-S.D.: 47+/-12 years; n=48), between 65 and 79 years (72+/-1 years; n=57), and from 80 years or older (84+/-1 years; n=23). Body mass index (BMI), renal and hepatic functions were similar in the three groups. A large interindividual variability of plasma levels of CIT (16-fold) and DCIT (12-fold) was measured for a given dose. The mean plasma levels of CIT corrected for a 20 mg daily dose were 55% higher in the very elderly (>=80 years) patients (65+/-30 ng/ml; p<0.001) and 38% higher in the elderly (65-79 years) patients (58+/-24 ng/ml; p<0.001) when compared to the adult patients (42+/-17 ng/ml). DCIT mean plasma level was 38% higher (p<0.05) in the group of very elderly patients (22+/-10 ng/ml) when compared to the adult patients (16+/-9 ng/ml). As a consequence, the mean plasma concentration of CIT+DCIT was 48% higher in the very elderly patients (86+/-36 ng/ml; p<0.001) and 33% higher in the elderly patients (77+/-28 ng/ml; p<0.001) when compared to the adult patients (58+/-21 ng/ml). Age correlated significantly with CIT (r=0.43, p<0.001), DCIT (r=0.28, p<0.01), and CIT+DCIT plasma levels (r=0.44, p<0.001), and thus accounts for 18% of the variability of CIT plasma levels, with no influence of gender. The recommended dose reduction of CIT in elderly patients seems therefore justified.

Aged↗
PubMed2005

Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients.

Clozapine, an atypical antipsychotic, depends mainly on cytochrome P4501A2 (CYP1A2) for its metabolic clearance. CYP1A2 is inducible by smoking, and lower plasma concentrations of clozapine are measured in smokers than in nonsmokers. Case reports have been published on the effects of discontinuing smoking in patients receiving clozapine, which might lead to elevated plasma concentrations and severe side effects. We present 2 cases on the consequences of smoking cessation in patients receiving this drug. In the first patient, smoking cessation resulted, within 2 weeks, in severe sedation and fatigue, with an approximately 3-fold increase of plasma clozapine concentrations. In the second patient, a very high plasma concentration of clozapine (3004 ng/mL) was measured 6 days following a 16-day stay in a general hospital, during which smoking was prohibited. In the latter patient, the replacement of omeprazole, a strong CYP1A2 inducer, by pantoprazole, a weaker CYP1A2 inducer, could have contributed, in addition to smoking cessation, to the observed strong increase of plasma clozapine concentrations. Genotyping of the 2 patients revealed that they were carriers of the AA genotype for the -164C>A polymorphism (CYP1A2*1F) in intron 1 of CYP1A2 gene, which has previously been shown to confer a high inducibility of CYP1A2 by smoking. Thus, at the initiation of clozapine treatment, smoking patients should be informed that, if they decide to stop smoking, they are encouraged to do so but must inform their prescriber beforehand. Also, because of the increased use of no-smoking policies in many hospitals, studies examining the consequences of such policies on the pharmacokinetics/pharmacodynamics of drugs metabolized by CYP1A2, taking into account different CYP1A2 genotypes, are needed.

Adult↗
PubMed2004

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Adult↗
PubMed2004

Pharmacokinetics of midazolam in CYP3A4- and CYP3A5-genotyped subjects.

OBJECTIVE: We investigated whether differences in pharmacokinetics of midazolam, a CYP3A probe, could be demonstrated between subjects with different CYP3A4 and CYP3A5 genotypes. METHODS: Plasma concentrations of midazolam, and of total (conjugated + unconjugated) 1'OH-midazolam, and 4'OH-midazolam were measured after the oral administration of 7.5 mg or of 75 micro g of midazolam in 21 healthy subjects. RESULTS: CYP3A5*7, CYP3A4*1E, CYP3A4*2, CYP3A4*4, CYP3A4*5, CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13, CYP3A4*17 and CYP3A4*18 alleles were not identified in the 21 subjects. CYP3A5*3, CYP3A5*6, CYP3A4*1B and CYP3A4*1F alleles were identified in 20, 1, 4 and 2 subjects, respectively. No statistically significant differences were observed for the AUC(inf) values between the different genotypes after the 75- micro g or the 7.5-mg dose. CONCLUSION: Presently, CYP3A4 and CYP3A5 genotyping methods do not sufficiently reflect the inter-individual variability of CYP3A activity.

Area Under Curve↗
PubMed2004

Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone.

BACKGROUND AND OBJECTIVES: Cytochrome P450 (CYP) 3A4 is the main CYP isozyme involved in methadone metabolism. We investigated the influence of grapefruit juice, which contains inhibitors of intestinal CYP3A, on the steady-state pharmacokinetics of methadone. METHODS: For 5 days, 8 patients undergoing methadone maintenance treatment received 200 mL water or grapefruit juice 30 minutes before and again together with their daily dose of methadone. Blood sampling for R-, S-, and R,S-methadone plasma determination was performed over a 24-hour period. CYP3A activity was determined by measuring the plasma 1'-hydroxymidazolam/midazolam ratio. RESULTS: A decrease in the midazolam ratio was measured in all patients after grapefruit juice (mean +/- SD before grapefruit juice, 9.3 +/- 5.9; mean +/- SD after grapefruit juice, 3.9 +/- 1.2; P <.05). Grapefruit juice led to a mean 17% increase in the area under the curve extrapolated to 24 hours for both enantiomers of methadone (range, 3% to 29% [P <.005]; range, -4% to 37% [P <.05]; and range, 1% to 32% [P <.01]; for R-, S-, and R,S-methadone, respectively). A similar increase in peak level and decrease in apparent clearance were measured with grapefruit juice, whereas time to peak level, terminal half-life, and apparent volume during the terminal phase of R-, S-, and R,S-methadone were not affected by grapefruit juice. No symptom of overmedication was either detected by the clinical staff or reported by the patients. CONCLUSIONS: Grapefruit juice administration is associated with a modest increase in methadone bioavailability, which is not expected to endanger patients. However, it cannot be excluded that a much stronger effect may occur in some patients, and thus grapefruit juice intake is not recommended during methadone maintenance treatment, in particular in patients initiating such a treatment.

Adult↗
PubMed2004

Chirality in the new generation of antidepressants: stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS.

Mirtazapine is an antidepressant that acts specifically on noradrenergic and sertonergic receptors. A LC-MS method was developed that allows the simultaneous analysis of the R-(-)- and S-(+)-enantiomers of mirtazapine (MIR), demethylmirtazapine (DMIR), and 8-hydroxymirtazapine (8-OH-MIR) in plasma of MIR-treated patients. The method involves a 3-step liquid-liquid extraction, an HPLC separation on a Chirobiotic V column, and MS detection in electrospray mode. The limit of quantification (LOQ) for all enantiomers was 0.5 ng/mL, and the intra- and interday CVs were within 3.3% to 11.7% (concentration ranges 5-50 ng/mL). A method is also presented for the quantitative analysis of glucuroconjugated MIR and 8-OH-MIR. S-(+)-8-OH-MIR is present in plasma mainly as its glucuronide. Preliminary data suggest that in all patients, except in those comedicated with CYP2D6 inhibitors such as fluoxetine and thioridazine, R-(-)-MIR concentrations were higher than those of S-(+)MIR. Moreover, fluvoxamine seems also to inhibit the metabolism of MIR. Therefore, this method seems to be suitable for the stereoselective assay of MIR and its metabolites in plasma of patients comedicated with MIR and other drugs for routine and research purposes.

Adult↗