Concentration-dose Ratio Research Articles

Relationship between UGT1A4 142T>G polymorphism and serum concentration of lamotrigine in Chinese epileptic patients: a meta-analysis

Objective: To investigate the relationship between the polymorphism of Uridine diphosphate glucuronosyltransferases (UGT)1A4 142T>G (*3, L48V, rs 2011425)and serum concentration of lamotrigine(LTG) in Chinese epileptic patients. Methods: Databases including Cochrane Library, PubMed, Embase, CNKI, VIP and Wanfang were searched for the studies on the relationship of the polymorphisms of UGT1A4 142T>G with concentration of LTG (from the establishment a database to December 1, 2017). Meta-analysis was performed by RevMan 5.3. Results: We pooled data from 6 literatures, including 903 Chinese epileptic patients. Meta-analysis: In terms of the effect of UGT1A4 142T>G polymorphism on the serum concentration/dose ratio(CDR)of LTG, there was no significant difference between the wild-type(TT genotype)group and mutant-type (TG+ GG genotype) group (MD=-0.08, 95% CI (-0.40-0.23)). Further subgroup analysis was performed on LTG monotherapy or valproic acid(VPA)co-administration. For patients treated with LTG as monotherapy, difference was not statistically significant between the 2 groups(MD=0.16, 95% CI(-0.25-0.57)). But in children treated with VPA co-administration, difference was statistically significant between the 2 groups (MD=-0.50, 95% CI(-0.75--0.26)). Conclusion: UGT1A4 142T>G polymorphism has an effect on LTG concentration only with VPA co-administration in Chinese epileptic pediatric patients and those children with wild-type (TT genotype) have a tendency to have a lower serum concentration of lamotrigine.

Risk Factors for Valproic Acid-induced Hyperammonaemia in Chinese Paediatric Patients with Epilepsy.

This study was aimed at identifying genetic and non-genetic risk factors for valproic acid (VPA)-induced hyperammonaemia in Chinese paediatric patients with epilepsy. A total of 210 epileptic patients, treated with VPA as monotherapy, were enrolled and classified into hyperammonaemia and control groups according to their blood ammonia level (cut-off value 50μmol/L). Serum concentrations of VPA and its major metabolites were simultaneously determined by ultrahigh-performance liquid chromatography-tandem mass spectrometry. Six single nucleotide polymorphisms in the candidate genes, CYP2C9, CYP2A6, CYP2B6 and CPS1, were analysed by a matrix-assisted laser desorption ionization-time of flight mass spectrometry method or nested PCR. Significant differences in age, aspartate transaminase level and the incidence of liver injury were observed between patients of hyperammonaemia and control groups. Genotype distributions of CYP2C9*3, CYP2A6*4 and CPS1 4217C>A allelic variants were also significantly different between the two groups. According to multiple regression analysis, a significant negative correlation was detected between age and the blood ammonia level, while liver injury, the concentration-dose ratio (CDR) of VPA and 2-propyl-4-pentenoic acid (4-ene VPA), and the presence of CYP2A6*4 or CPS1 4217C>A showed positivecorrelationswith the blood ammonia level. In addition, the risk factors for hyperammonaemia identified by logistic regression analysis were as follows: a younger age (odds ratio [OR]=0.85; 95% confidence interval [CI]=0.76-0.96; p=0.007), occurrence of liver injury (OR=4.60; 95% CI=1.27-16.74; p=0.021), higher CDR of 4-ene VPA (OR=1.08; 95% CI=1.03-1.14; p=0.001), and carrying mutant alleles of CYP2C9*3 (OR=3.42; 95% CI=1.15-10.19; p=0.028), CYP2A6*4 (OR=3.23; 95% CI=1.40-7.48; p=0.006) and CPS1 4217C>A (OR=3.25; 95% CI=1.52-6.94; p=0.002). Our findings indicated that multiple genetic and non-genetic risk factors that were identified can be used to predict the development of VPA-induced hyperammonaemia in Chinese paediatric patients with epilepsy.

Bioavailability and costs of once-daily and twice-daily tacrolimus formulations in de novo kidney transplantation.

The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12months. Intrapatient variability in trough levels and C/D ratios after 3months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P=.003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

The clinical significance of the lamotrigine pharmacokinetic variability

To estimate pharmacokinetic variability of lamotrigine (LTG) and its clinical significance. One hundred patients, including 74 women, aged from 18 to 77 years (38.23±14.37 years), with focal epilepsy were examined. Monotherapy with LTG was administered to 54 patients, duotherapy to 46 patients (LTG and valproic acid combination to 27 patients, LTG and liver enzymes inducers to 19 patients). Patients underwent procedures of therapeutic drug monitoring (TDM). Minimal (Cssmin) and maximal (Cssmax) steady-state LTG plasma concentrations, and concentration-to-weight ratio (CDR) were calculated. In patients who used LTG in monotherapy, LTG Cssmin was 5.6±4.65 mg/l, Cssmax 7.59±5.54 mg/l. In the group that received LTG in combination with valproate, LTG Сssmin was 7.8 [5.4; 11.8] mg / l and Cssmax 11.4 [7.3; 15.3] mg/l. In the group that received LTG in combination with drug-inducers of glucuronidation, Cssmin was 2.5 [1.99; 4.32] mg/l, Cssmax 4.73 [2.91; 6.70] mg/l. Statistically significant differences in CDR parameter between groups with LTG monotherapy and duotherapy, both with inducer and with inhibitors, as well as between groups of duotherapy with inductors and with inhibitors were obtained. The results of the study indicate a pronounced pharmacokinetic variability of the LTG. Conducting TDM allows the establishment of individual therapeutic concentrations of LTG in blood plasma and setting a correction vector for antiepileptic therapy.

The relationship between tacrolimus concentration-dose ratio and genetic polymorphism in patients subjected to renal transplantation

Background/Aim. Tacrolimus concentration-dose ratio as a potential therapeutic drug monitoring strategy was suggested to be used for the patients subjected to renal transplantation. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio, suggested to be used as a therapeutic drug monitoring strategy and the polymorphisms of genes encoding the most important enzymes, such as CYP3A5 and CYP3A4, as well as the transporter P-glycoprotein, for its metabolism and elimination. Methods. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 Real- Time PCR System by assessing allelic discrimination based on TaqMan? methodology. Results. Patients (n = 13) who were treated with less than 2 mg of tacrolimus/day (0.024 ? 0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/mL/mg/kg. In this group, 84.62% patients had CYP3?5 *3*3 allele. All of these patients had CYP3?4 *1*1/*1*1B allele. Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant, while 69.23% of our patients had CC and CT gene variants. Conclusion. Tacrolimus concentration-dose ratio greater than 150 ng/mL/mg/kg is cut-off value in patients subjected to renal transplantation which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein.

Relationship Between Genetic Polymorphism and Tacrolimus Concentration-Dose Ratio in Renal Transplant Patients

Tacrolimus concentration-dose ratio, as a potential therapeutic drug monitoring strategy, has been suggested to be used for the renal transplant patients. The aim of this study was examining the relationship between tacrolimus concentration-dose ratio and the polymorphisms of genes encoding the most important enzymes, such as CYP3A4/5, as well as the transporter P-glycoprotein, for its metabolism and elimination. The study was designed as a prospective case series study, in which the unit of monitoring was the outpatient examination of 54 patients subjected to renal transplantation. Genotyping was performed by 7500 Real-Time PCR System by assessing allelic discrimination based on TaqMan® methodology. Patients who were treated with less than 2 mg of tacrolimus/day (0.024±0.006 mg/kg/day) had the tacrolimus concentration-dose ratio larger than 150 ng/ml/mg/kg. In this group, 84.62% patients had CYP3A5 *3*3 allele (CYP3A5 nonexpressers). All of these patients had CYP3A4 *1*1/*1*1B allele (CYP3A4 expressers). Regarding ABCB1 C3435T gene, 30.77% of patients had the TT gene variant (diminished activity of ABCB1 transporter), while 69.23% of our patients had CC and CT gene variants. Tacrolimus concentration-dose ratio greater than 150 ng/ml/mg/kg is cut-off value in renal transplant patients which might point to patients who are poor CYP3A5 metabolizers and/or with dysfunctional P-glycoprotein.

Association between PK/PD-involved gene polymorphisms and carbamazepine-individualized therapy.

To evaluate the association between the major genetic variants involved in the pharmacokinetic/pharmacodynamic (PK/PD) properties of carbamazepine (CBZ) and its maintenance doses and concentrations. The genotypes of 166 patients receiving CBZ monotherapy were detected using high-resolution melting curve (HRM) and TaqMan methods. Both univariate and multiple regression analyses revealed that carriers of the SCN1A IVS5-91G>A or EPHX1 c.337T>C allele tended to require a higher CBZ dose and a lower CBZ natural logarithmic concentration-dose ratio (lnCDR) than noncarriers (p < 0.05). Furthermore, two interactions between these genes were associated with the lnCDR and the maintenance dosage of CBZ, respectively. SCN1A IVS5-91G>A gene polymorphism is potential genetic biomarker associated with the PK of CBZ.

Genome-wide association study identifies common variants associated with pharmacokinetics of psychotropic drugs.

Individual variation in pharmacokinetics of psychotropic drugs, particularly metabolism, is an important factor to consider in pharmacological treatment in psychiatry. A large proportion of this variance is still not accounted for, but evidence so far suggests the involvement of genetic factors. We performed a genome-wide association study (GWAS) with concentration dose ratio (CDR) as sub-phenotype to assess metabolism rate of psychotropic drugs in a homogenous Norwegian sample of 1334 individuals diagnosed with a severe mental disorder. The GWAS revealed one genome-wide significant marker (rs16935279, p-value=3.95×10(-10), pperm=7.5×10(-4)) located in an intronic region of the lncRNA LOC100505718. Carriers of the minor allele have a lower metabolism rate of antiepileptic drugs compared to major allele carriers. In addition, several nominally significant associations between single nucleotide polymorphisms (SNPs) and CDR for antipsychotic, antidepressant and antiepileptic drugs were disclosed. We consider standardised CDR to be a useful measure of the metabolism rate of a drug. The present findings indicate that common gene variants could affect the metabolism of psychotropic drugs. This warrants further investigations into the functional mechanisms involved as it may lead to identification of predictive markers as well as novel drug targets.

Meta-analysis of the effect of MDR1 C3435 polymorphism on tacrolimus pharmacokinetics in renal transplant recipients

BackgroundThe published data revealed conflicting results of the polymorphism of MDR1 exon 26 SNP C3435T on the pharmacokinetics of tacrolimus in different post transplant times; thus, the aim was to perform a meta-analysis of different post transplant times to investigate the influence of SNP C3435T on the tacrolimus pharmacokinetics. MethodsA literature search was conducted to locate the relevant papers by using the PUBMED and EMBASE electronic source until 2011. The pharmacokinetic parameters, including dose administration, concentration and concentration to dose ratio were extracted and a meta-analysis was performed by using STATA10.0. ResultsA total of 13 papers concerning 1327 individuals were included in the meta-analysis. The overall results showed SNP C3435T could influence the pharmacokinetic parameters in different post transplant times, the subjects with CC genotype had lower concentration dose ratio and need higher tacrolimus dose than the CT and TT genotype. ConclusionsOur meta-analysis of available studies has demonstrated a definite correlation between the SNP C3435T in MDR1 gene and pharmacokinetics of tacrolimus. However, additional studies with large sample size and better study designs are warranted to verify our finding.

Association of Polymorphisms in EPHX1 , UGT2B7 , ABCB1 , ABCC2 , SCN1A and SCN2A Genes with Carbamazepine Therapy Optimization

Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations. Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5-91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration-dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration-dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration-dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration-dose ratio of CBZ (adjusted r(2) = 55%). The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results.

Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies

Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P < 0.001), fluoxetine (P < 0.001) and paroxetine (P = 0.011) dose-dependent increases and levomepromazine an increase related to its serum concentration (P < 0.001). Results for injected zuclopenthixol were similar but not all reached statistical significance. The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure.

Micafungin Does Not Influence the Concentration of Tacrolimus in Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs. Objective To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation. Results The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 ± 306, 653 ± 328, 699 ± 340 and 671 ± 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 ± 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%. Conclusion We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients.

Body Mass Index and Weight Gain as Alternative or Complementary Hypothesis to Explain Olanzapine Concentration-Dose Ratio Accumulation

Body Mass Index and Weight Gain as Alternative or Complementary Hypothesis to Explain Olanzapine Concentration-Dose Ratio Accumulation

Assessment of the Prescription of Antidepressant Drugs in Elderly Nursing Home Patients

The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Ostergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

The Relationship Between the Response of Clinical Symptoms and Plasma Olanzapine Concentration, Based on Pharmacogenetics

The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics.

Correlation between Cyclosporine Blood Concentration-Dose Ratio and Biochemical Parameters in Living-Donor Lung Transplant Patients

Lung transplantation has proved to be an effective treatment worldwide for a variety of end-stage lung diseases.In Japan,living-donor lung transplantation is the predominant procedure used.In this and other types of transplantation,the calcineurin inhibitor cyclosporine (CYA) is frequently used as an immunosuppressive drug.However,this drug requires strict control of dosing to minimize the risk of rejection and over-immunosuppression,and for the orally administered drug,interand intra-individual bioavailability vary widely.Intensive drug monitoring is therefore necessary.In this study,25 patients who received lung allografts from living donors between October 1998 and January 2006 at Okayama University Hospital were investigated to see if there was any correlation between the CYA concentration-dose ratio and biochemical parameters.The most significant correlation was between the CYA concentration-dose ratio and total cholesterol,with a correlation coefficient of 0.46.As for individual results in this respect,14 of 25 patients had a correlation coefficient of 0.5 or greater,and the highest was 0.92.There was thus a definite correlation between the CYA concentration-dose ratio and total cholesterol in patients who had undergone living-donor lung transplantation.

Micafungin Does Not Influence the Concentration of Tacrolimus in Patients after Allogeneic Hematopoietic Stem Cell Transplantation.

Purpose: Tacrolimus (Tac) is commonly used for stem cell transplant (SCT) recipients as an agent for prophylaxis of graft-versus-host disease (GVHD) and because of its narrow therapeutic index a close drug monitoring is needed. Micafungin (MCFG) is widely used as a strong antifungal agent in empirical therapy for patients with febrile neutropenia. Both Tac and MCFG are substrates of CYP3A4 in vitro. Therefore, there is a risk of drug interaction by the coadministration of these 2 agents.Methods: Five consecutive Japanese patients (3 males and 2 females) with hematological malignancies who received allogeneic SCT in our hospital between August 2005 and December 2006 were enrolled in this study. We estimated the drug interaction of Tac and MCFG by evaluating the pharmacokinetics in 5 cases of allogeneic SCT. The patients initially received 24 hour continuous intravenous administration of Tac at 0.01 mg/kg. The dose was then adjusted to a concentration between 10–12 ng/ml by monitoring of the concentration 3 times a week. MCFG was started at 150 mg/body/day as an empirical therapy in order to manage the neutropenic fever suggesting fungal infection. MCFG was administered as a one hour infusion. For the determination of both Tac and MCFG concentration, serial blood samples were drawn from the patients at 1, 4, 8 and 24 hours after the initiation of therapy. Tac concentrations were determined by the microparticle enzyme immunoassay method using an IMx Tacrolimus II analyzer (Abbott Diagnostics, Abbott Park, IL). The concentration of MCFG in blood was analyzed by high performance liquid chromatography (HPLC). HPLC was performed using a Phenomenex Luna 3μ C18 column (4.6 mm x 150 mm) as an analytical column.Results: Five patients were included in this study; 3 were male and 2 were female. The age of patients ranged from 37 to 71 years, with a median age of 53 years. The donor source was unrelated bone marrow (BM) in 1 patient, peripheral blood stem cells (PBSC) from a related donor in 1 patient, and cord blood (CB) in 3 patients. The mean value of the concentration/dose (CD) ratio of Tac in all patients administered concomitant MCFG was 704.7 ± 61.8 ((ng/mL)/(mg/(kg x day)) and the value without MCFG was 710.3 ± 390.4 ((ng/mL)/(mg/(kg x day)). The proportion of the CD ratio in patients treated with Tac and MCFG to the CD ratio in patients treated with Tac alone was 0.886, 0.960, 1.08 and 1.04 for 1, 4, 8 and 24 hours, respectively. For both Tac and MCFG, the 90% confidence intervals for the primary PK parameters (i.e., the CD ratio at each time point) ranged from 80% to 125%. The concentrations of MCFG at 1, 4, 8 and 24 hours after the start of infusion were 27.3, 20.0, 16.7 and 9.4, respectively. Pharmacokinetic parameters of MCFG was following; AUC (area under the curve) 368 ± 172 mg x hr/L, Vd (distribution volume in elimination phase) 0.223 ± 0.106 L/kg, clearance 0.0088 ± 0.003 L/(hr x kg) and elimination half life 18.3 ± 1.7 hr.Conclusion: We concluded that there was no drug interaction between Tac and concomitantly administered MCFG in SCT recipients.

Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability. We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1'-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring. Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration-dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1'-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively. The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 +/- 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.

Atypical antipsychotic dosing: the effect of smoking and caffeine.

Aprevious Psychopharmacology column focused on the effect of co-prescribing anticonvulsant inducers with atypical antipsychotics and argued that the dosing recommendations for atypical antipsychotics that are provided on package inserts do not apply well to patients with unusual genetic profiles or to patients who are exposed to environmental factors that change the concentration-dose ratio (C/D) (1). Severe mental illnesses are associated with tobacco smoking and, among smokers, with heavy smoking. Is smoking relevant to atypical antipsychotic dosing? Certainly. Byproducts of tobacco smoking, particularly the polycyclic aromatic hydrocarbons, are metabolic inducers. These byproducts are inducers of the cytochrome P450 isoenzyme 1A2 (CYP1A2) and of the less understood UDP-glucuronosyltransferases (UGTs). The metabolic inductive effects are not specific to tobacco smoking; they can also be expected from marijuana smoking. Because inducers require the synthesis of new enzymes, several weeks are usually needed before the maximum effects of inducers are seen. Inducers’ effects may take a few weeks to disappear as well. The case reports of clozapine’s toxicity after smoking cessation suggest that the inductive effects of smoking take at least two to four weeks to disappear (Table 1). The studies listed in Table 1 suggest that smoking’s inductive effects may be relevant for clinicians who prescribe atypical antipsychotics. Additional pharmacologic support of the relevance of smoking’s inductive effects comes from caffeine intake studies. Caffeine, a drug that is more than 90 percent dependent on CYP1A2 for its metabolism and that is widely used in the United States, can exemplify smoking’s effects on drug metabolism. The C/D of caffeine appears to be threefold to fourfold as high among nonsmokers compared with smokers. This higher ratio means that smokers need three to four times the caffeine “dosage” as nonsmokers on average to get the same plasma caffeine levels. In a caffeine intake study of 147 outpatients with schizophrenia who drank caffeine, the average caffeine intake was 1.3 mg per kg a day for nonsmokers, 2.7 mg per kg a day for nonheavy smokers (less than 1.5 packs a day), and 3.4 mg per kg a day for heavy smokers (1.5 packs a day or more) (2).

Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation

We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 ± 125.3 (average ± SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 ± 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 ± 385.4 mg/d, average ± SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant. (Liver Transpl 2003;9:1108-1113.)