Effect of UGT1A4, UGT2B7, UGT2B15, UGT2B17 and ABC1B polymorphisms on lamotrigine metabolism in Danish patients.

OBJECTIVE: To evaluate the impact of genetic polymorphisms of UGT enzymes (UGT1A4, UGT2B7, UGT2B15 and UGT 2B17) and the transporter protein ABCB1 on Lamotrigine (LTG) metabolism. METHODS: Single nucleotide polymorphisms UGT1A4*2 (P24T, c.70C>A), UGT1A4*3 (L48V c.142T>G), UGT2B7*2 (H802Y, c.802C>T), UGT2B15*2 (Y85D, c.253G>T), UGT2B17 deletion and transporters ABC 1236C> T and 3435C> T were determined in 337 Caucasian patients with epilepsy treated with LTG in Denmark. The prospectively collected data included LTG dosage, LTG plasma concentration, 2-N-GLU concentration, sex, smoking habits, concomitant medicine, oral contraceptives (OC). RESULTS: The non-smokers with LTG monotherapy and LTG polytherapy with other non-interacting drugs NIAEDs (n = 199) were analyzed separately in univariant analyses. LTG ratios (LTG plasma concentration/ (LTG dose/weight)) in patients carrying wild type UGT1A4*2 C-allele were 22% lower than in heterozygous C-carriers (p = 0.013). Patients with UGT2B7*2 polymorphism TT genotype had 1.2-fold higher LTG ratios (p = 0.0078) and 0.78-fold lower GLU/LTG ratio (p = 0.0275) than patients homozygous for the C allele. The similar significant findings were also seen comparing homozygotes (TT) with heterozygotes patients (CT). Individuals homozygous for the UGT2B15*2 T allele displayed 18% lower LTG ratio concentrations than individuals homozygous for the G allele (p = 0.014),while significant difference in GLU/LTG ratio was only seen comparing wild type with homozygous patients (GG versus TT, p = 0.031). A copy number variation gene deletion polymorphism of UGT2B17 showed that individuals devoid of the gene (del/del) exhibited 1.3-fold higher LTG ratio (p = 0.015). For ABCB1c.1236 C>T and ABC1B1c.3435 C>T no associations with LTG and GLU ratios were found. Sex specific differences in enzyme activity (most prominent effect in women) on LTG metabolism were found for UGT2B15, UGT2B17, UGT1A4 and UGT2B7 polymorphisms. Multiple regression analysis confirmed the significant effect of OC, VPA and UGT1A4 * 2 and UGT2B7 * 2 on LTG metabolism. CONCLUSION: Our study confirms the previous findings that genetic variations in UGT2B7 and UGT1A4 genes are associated with serum LTG concentrations. Furthermore, our results indicate that it is possible that different UGT genotypes may exert larger impact on LTG metabolism in women than in men.

Signal Detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and Use of VigiBase as a Complementary Source of Reference.

INTRODUCTION: Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications. AIMS: This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals. METHODS: Signals of medication-congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation. RESULTS: EUROmediCAT analysis identified 49 signals of medication-congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly. CONCLUSION: EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

Opioid maintenance treatment of pregnant women in the Scandinavian countries.

Background: WHO guidelines emphasise the need for descriptions of clinical practice and observational studies on risk and benefits of pharmacotherapies in pregnancy. The aims of the present study were to: (1) Describe opioid maintenance treatment (OMT) in the Scandinavian countries in general, and specifically for pregnant women, (2) Describe a project which utilises a new approach using registry-linkage data to examine associations between prenatal exposure to OMT and child outcomes: a Scandinavian cohort study of pregnant women in OMT during pregnancy (ScopeOMT). Data: Guidelines describing the treatment of persons with opioid use disorders in general, and specifically for pregnant women. Scandinavian registry-linkage data from ScopeOMT. Results: Registry data show that approximately 800 pregnant women received OMT during pregnancy in the period of the ScopeOMT study. Similarities across the Scandinavian countries include access to free healthcare and treatment; multidisciplinary teams trained to support pregnant women in OMT; buprenorphine as the recommended drug when initiating therapy; and a holistic focus on the patients' lives. An important difference is that Norwegian women who use illegal substances that may harm the foetus may be admitted - voluntarily, or against their will - for parts of, or the remainder of the pregnancy to inpatient treatment at specialised clinics. Conclusion: Many similarities in the treatment provided to opioid-dependent persons in the Scandinavian countries place this area in an excellent position to combine the efforts and carry out observational studies concerning the safety of OMT during pregnancy.

Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival.

BACKGROUND: The incidence of narcolepsy rose sharply after the swine influenza A (H1N1) vaccination campaign with Pandemrix. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. The most frequent form is strongly associated with HLA-DQB1*06:02, but only a minority of carriers develop narcolepsy. We aimed to identify genetic markers that predispose to Pandemrix-induced narcolepsy. METHODS: We tested for genome-wide and candidate gene associations in 42 narcolepsy cases and 4981 controls. Genotyping was performed on Illumina arrays, HLA alleles were imputed using SNP2HLA, and single nucleotide polymorphisms were imputed using the haplotype reference consortium panel. The genome-wide significance threshold was p < 5 × 10-8, and the nominal threshold was p < 0.05. Results were replicated in 32 cases and 7125 controls. Chromatin data was used for functional annotation. FINDINGS: Carrying HLA-DQB1*06:02 was significantly associated with narcolepsy, odds ratio (OR) 39.4 [95% confidence interval (CI) 11.3, 137], p = 7.9 × 10-9. After adjustment for HLA, GDNF-AS1 (rs62360233) was significantly associated, OR = 8.7 [95% CI 4.2, 17.5], p = 2.6 × 10-9, and this was replicated, OR = 3.4 [95% CI 1.2-9.6], p = 0.022. Functional analysis revealed variants in high LD with rs62360233 that might explain the detected association. The candidate immune-gene locus TRAJ (rs1154155) was nominally associated in both the discovery and replication cohorts, meta-analysis OR = 2.0 [95% CI 1.4, 2.8], p = 0.0002. INTERPRETATION: We found a novel association between Pandemrix-induced narcolepsy and the non-coding RNA gene GDNF-AS1, which has been shown to regulate expression of the essential neurotrophic factor GDNF. Changes in regulation of GDNF have been associated with neurodegenerative diseases. This finding may increase the understanding of disease mechanisms underlying narcolepsy. Associations between Pandemrix-induced narcolepsy and immune-related genes were replicated.

Long-acting olanzapine injection during pregnancy and breastfeeding: a case report.

We present one case of a woman treated with the intramuscular depot formulation of the atypical antipsychotic, olanzapine pamoate (ZypAdhera®), during pregnancy and breastfeeding. Data on olanzapine distribution in breast milk as well as on plasma concentration in the nursed infant are provided. The present case report demonstrates that olanzapine was excreted in the breast milk, but the breast-fed infant had very low olanzapine concentrations, which did not result in any adverse effects.

UGT polymorphisms and lamotrigine clearance during pregnancy.

OBJECTIVE: To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP). METHODS: Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus. RESULTS: Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between -53% and -74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: -53% (95%CI: -68% to -39%) versus -65% (95%CI: -69% to -60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were -64% in T2 (95%CI: -69% to -59%) and -67% in T3 (95%CI: -71% to -63%) in women who expected a female child compared to whose with a male child -58% in T2 (p = 0.002, 95%CI: -67% to -48%) and -57% in T3 (p < 0.001, 95%CI: -65% to -48%). CONCLUSION: Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance.

Narcolepsy Treated with Racemic Amphetamine during Pregnancy and Breastfeeding.

This case report describes a woman with narcolepsy treated with racemic amphetamine (rac-amphetamine) during pregnancy and breastfeeding with follow-up on the infant's development up to 10 months of age. The pregnancy outcome and the pharmacokinetics of rac-amphetamine were studied during breastfeeding. The pregnancy and the delivery were uneventful. Concentrations of rac-amphetamine were determined in the plasma of the mother and infant, and in the breast milk with a liquid chromatography-mass spectrometry method. Samples were obtained at 2, 5, and 9 weeks postpartum. The transfer of rac-amphetamine to the breast milk was extensive (mean milk/maternal plasma concentration ratio approximately 3). The breastfed infant had a low plasma concentration of rac-amphetamine (about 9% of the maternal plasma level) and the calculated relative infant dose was low (2%). No adverse effects were observed in the breastfed infant. The infant's somatic and psychomotor development up to 10 months of age was normal. Further studies of amphetamine prescribed for medical reasons during pregnancy and lactation are needed.

Zonisamide: pharmacokinetics, efficacy, and adverse events in children with epilepsy.

BACKGROUND: Zonisamide is a new generation antiepileptic drug (AED) widely used in children with refractory epilepsy, although until recently, it was used to a large extent as off-label or unlicensed medication due to the lack of evidence-based studies. Children have a different pharmacokinetic profile than adults and an adult dose regimen cannot be directly translated into pediatric use. Patients and METHODS: In this retrospective noninterventional study of the medical records of 75 children with pharmacoresistant epilepsy, the pharmacokinetics, efficacy and safety of zonisamide were examined. The dose-to-concentration ratio, the daily weight-normalized dose of zonisamide divided by its plasma concentration, was used as a measure of clearance. In addition, data on the efficacy of zonisamide to reduce seizures and reported adverse events were extracted from the medical records and analyzed. RESULTS: Young children (range, 0-4 years) had a significantly increased zonisamide clearance compared with older ones (range, 5-17 years) and those with enzyme-inducing comedication (carbamazepine, phenobarbital, or phenytoin) had increased clearance compared with those on nonenzyme inducers; the increases were 1.7-fold and 1.8-fold, respectively. No significant difference in clearance was found between female and male subjects. The clearances of concomitant AEDs were not affected by zonisamide administration. The overall efficacy of zonisamide for reducing seizure frequency ≥ 50% was 35% and the most frequent adverse event was fatigue, reported in 23% of the patients. CONCLUSION: Patients with enzyme-inducing comedication or of young age (range, 0-4 years) might need higher weight-normalized doses to achieve the same plasma levels as in patients with no enzyme-inducing comedication or patients of older age. Zonisamide was not found to influence the pharmacokinetics of concomitant AEDs. The shortage of pharmacokinetic studies of zonisamide in children highlights the need for research of this kind.

Opioid-related mortality and filled prescriptions for buprenorphine and methadone.

INTRODUCTION AND AIMS: To assess opioid-related mortality and correlation with filled prescriptions for buprenorphine and methadone. DESIGN AND METHODS: A register study, including data from the Swedish Forensic Pathology and Forensic Toxicology databases 2003-2010, the Prescribed Drug Register and the National Patient Register. RESULTS: A total of 1301 deaths, assessed as related to buprenorphine, methadone or heroin, or a combination of them, were studied. The largest number of fatalities was related to intake of heroin (n = 776), followed by methadone (n = 342) and buprenorphine (n = 168). The total annual number of fatal cases related to the studied drugs more than doubled (116 to 255) during the study period. There were increases in mortality related to both buprenorphine and methadone: from 1 to 49 cases for buprenorphine, and from 19 to 81 cases for methadone. Only one-fifth of the fatal cases had a filled prescription for the maintenance drug assessed as the cause of death. DISCUSSION AND CONCLUSION: This study showed that most fatalities were not related to filled prescriptions of maintenance drugs, and a substantial illicit use of buprenorphine and methadone resulting in deaths was revealed. To prevent opioid toxicity deaths it is important to make efforts not only to reduce drug diversion from maintenance programs, but also to improve the control of drug trafficking and other illegal sources.

Direct and efficient liquid chromatographic-tandem mass spectrometric method for opiates in urine drug testing - importance of 6-acetylmorphine and reduction of analytes.

Opiates comprise a class of abused drugs that is of primary interest in clinical and forensic urine drug testing. Determination of heroin, codeine, or a multi-drug ingestion is complicated since both heroin and codeine can lead to urinary excretion of free and conjugated morphine. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) offers advantage over gas chromatography-mass spectrometry by simplifying sample preparation but increases the number of analytes. A method based on direct injection of five-fold diluted urine for confirmation of morphine, morphine-3-glucuronide, morphine-6-glucuronide, codeine, codeine-6-glucuronide and 6-acetylmorphine was validated using LC-MS/MS in positive electrospray mode monitoring two transitions using selected reaction monitoring. The method was applied for the analysis of 3155 unknown urine samples which were positive for opiates in immunochemical screening. A linear response was observed for all compounds in the calibration curves covering more than three orders of magnitude. Cut off was set to 2 ng/ml for 6-acetylmorphine and 150 ng/ml for the other analytes. 6-Acetylmorphine was found to be effective (sensitivity 82%) in detecting samples as heroin intake. Morphine-3-glucuronide and codeine-6-glucuronide was the predominant components of total morphine and codeine, 84% and 93%, respectively. The authors have validated a robust LC-MS/MS method for rapid qualitative and quantitative analysis of opiates in urine. 6-Acetylmorphine has been demonstrated as a sensitive and important parameter for a heroin intake. A possible interpretation strategy to conclude the source of detected analytes was proposed. The method might be further developed by reducing the number of analytes to morphine-3-glucuronide, codeine-6-glucuronide and 6-acetylmorphine without compromising test performance.

Rufinamide in children with refractory epilepsy: pharmacokinetics, efficacy, and safety.

We examined the influence of age and type of concomitant antiepileptic drugs (AEDs) on the pharmacokinetics of rufinamide (RUF) as well as its efficacy and safety in 51 children with refractory epilepsy. In a retrospective noninterventional survey, dose-to-concentration ratios of RUF and concomitant AEDs were calculated: the weight-normalized dose (mg/kg/d) divided by the steady-state trough plasma drug level, which was used as a measure of clearance. During treatment with RUF concomitantly with valproic acid (VPA) young children, aged 0 to 4.9 years, had a low clearance of RUF, which did not differ from older children. If not on VPA but on enzyme inducers, young children had a threefold higher clearance of RUF than the older ones. In young children not on VPA, those on enzyme inducers had 1.7-fold higher clearance than those on nonenzyme inducers. In children neither on VPA nor on enzyme inducers, RUF clearance was age-dependent with higher clearance in younger children. Adding RUF did not change the pharmacokinetics of concomitantly used AEDs. Seizure response after 2 to 3 months on RUF treatment was found in 12 of 51 children (23.5%), at mean plasma level of 36.9 ± 22.0 µmol/L. Adverse events were reported in 41% of the patients of which fatigue was most frequent (24%).

Age and comedications influence levetiracetam pharmacokinetics in children.

The pharmacokinetics of many antiepileptic drugs differs between adults and children. The influence of age and concomitant medications on the dose/concentration ratio of levetiracetam was examined in 103 children with epilepsy. Dosing and plasma levels of levetiracetam and concomitant antiepileptic drugs were reviewed retrospectively. The dose/concentration ratio was calculated as the weight-normalized dose (mg/kg/day) divided by the steady-state trough plasma drug level, which was used as a measure of apparent oral clearance of levetiracetam. Children were classified into age groups and treatment groups: levetiracetam given with enzyme inducers (n = 24) or nonenzyme inducers (n = 69), or as monotherapy (n = 10). Levetiracetam clearance differed significantly between age groups (0-4, 5-11, and 12-17 years), i.e., the younger the child, the higher the clearance. The increase was 1.7-fold between the youngest and oldest age groups. Children on enzyme inducers exhibited significantly higher clearance (1.3-fold), compared with those on nonenzyme inducers and monotherapy. Levetiracetam did not influence the clearance of lamotrigine, valproate, topiramate, or clonazepam. In conclusion, younger age and comedication with an enzyme inducer increased levetiracetam clearance. This finding should be taken into account when treating individual patients.

Are lamotrigine kinetics altered in menopause? Observations from a drug monitoring database.

To assess possible alterations in the pharmacokinetics of lamotrigine (LTG) in menopause, we reviewed the database of the drug monitoring service at the Karolinska University Hospital. Dose/plasma concentration (D/C) ratios of LTG in different age groups of women under treatment with LTG were compared with ratios for men. For further comparison, D/C ratios were calculated for men and women treated with carbamazepine (CBZ). D/C ratios were available for 752 men and 1115 women on LTG, and for 3464 men and 3088 women on CBZ. The D/C ratios of CBZ were very similar among men and women in all age groups under study. In contrast, LTG D/C ratios seemed to decline in women 51-55 years of age, and were in this age group significantly lower among women than among men (P<0.05). Our data suggest that there may be a transient decline in clearance of LTG in conjunction with presumed menopause.

Pharmacokinetics of topiramate during pregnancy.

PURPOSE: To study the effects of pregnancy on plasma concentrations of topiramate (TPM). METHODS: An established routine fluorescence polarization immunoassay (FPIA) method was used to determine TPM concentrations in 15 women with epilepsy treated with TPM during altogether 17 pregnancies. RESULTS: In 10 pregnancies, where samples were available from all three trimesters, the mean TPM dose/concentration ratio (D/C-ratio) was significantly higher than outside pregnancy baseline value 37.3 L/day (+/-15.9), during the 2nd, 67.5L/day (+/-23.4), and the 3rd trimester, 65.1L/day (+/-30.4), but not during the 1st, 49.4 L/day (+/-29.4). Including seven additional pregnancies enrolled late with data only from the 3rd trimester, the mean D/C-ratio during the 3rd trimester was 67.4 L/day (+/-27.5) compared to baseline, 38.8L/day (+/-18.0), an average increase by 71.8%. There was a pronounced intra-individual variability in alterations in D/C-ratios during pregnancies. CONCLUSIONS: Our data show a significant pregnancy-related increase in D/C-ratios of TPM suggesting that therapeutic drug monitoring might be of value.

Effects of pregnancy and contraception on lamotrigine disposition: new insights through analysis of lamotrigine metabolites.

OBJECTIVE: To investigate possible underlying mechanisms for alterations in lamotrigine (LTG) kinetics by gestation and use of contraceptives. METHODS: Plasma concentrations of LTG and its main metabolite lamotrigine-2-N-glucuronide (2-N-GLUC) were measured in 31 women on LTG taking combined oral contraceptives (COC), in 12 with contraceptive intrauterine devices containing levonorgestrel (CIUD), and in 20 on LTG without hormonal contraception (controls). We also measured the levels of LTG and 2-N-GLUC in plasma and urine in eight women during pregnancy, and up to three months postpartum. LTG levels in plasma were measured by high-performance liquid chromatography method (HPLC) and N-2-GLUC in urine and plasma and LTG in urine by liquid chromatography-mass spectrometry (LC/MS). RESULTS: There were no significant differences in LTG dose/concentration (D/C), or N-2-GLUC/LTG ratios between women with CIUD and controls. In contrast, compared to controls, the LTG D/C ratio was 56% higher in women taking COC (mean+/-SD, 83+/-47 versus 53.0+/-24.2; p<0.01) and N-2-GLUC/LTG ratio 82% higher in women taking COC (mean 0.477+/-0.212 SD versus 0.262+/-0.127; p<0.0003. The 2-GLUC/LTG ratios were 154% higher in plasma and 122% higher in urine in late pregnancy compared with baseline 3months postpartum. CONCLUSIONS: Our data indicate that the alterations in LTG kinetics in pregnancy as well as those induced by COC are mainly explained by enzymatic induction of the N-2-glucuronide pathway. In addition we found no evidence for an interaction between LTG and CIUD.

Plasma concentrations of lamotrigine and its 2-N-glucuronide metabolite during pregnancy in women with epilepsy.

OBJECTIVE: To further characterize pregnancy-induced alterations in the pharmacokinetics of lamotrigine (LTG). METHODS: Fifteen women treated with LTG were studied during 17 pregnancies. Complete trough blood samples from all trimesters and baseline > 1 month after delivery were available for 12 pregnancies (Group A), whereas, five contributed with samples only from the third trimester and baseline (Group B). High-performance liquid chromatography (HPLC) was used to determine LTG plasma concentrations, and liquid chromatography-mass spectrometry to assay the main metabolite 2-N-lamotrigine glucuronide (2-N-GLUC) in plasma. RESULTS: In group A, the mean dose/plasma concentration ratio (D/C) of LTG at baseline after pregnancy was 66.5 +/- 17.9 (+/- SD) L/day and approximately 250% higher in late pregnancy. The mean lamotrigine-2-N-glucuronide/lamotrigine plasma concentration ratio (2-N-GLUC/LTG) was 0.349 +/- 0.141 (+/- SD) at baseline and 147% higher in late pregnancy. Taking group A and B together, the 2-N-GLUC/LTG ratio was 175% higher in the third trimester compared to baseline. CONCLUSION: Our study confirms a significant decline in LTG plasma levels during pregnancy in women on monotherapy with LTG. An increased 2-N-GLUC/LTG ratio suggests that this decline may be related to an increased metabolism of LTG by glucuronidation.

Oral contraceptives induce lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial.

PURPOSE: This study evaluates the effect of oral contraceptives on lamotrigine (LTG) plasma concentrations and urine excretion of LTG metabolites in a double-blind, placebo-controlled, crossover study in patients with epilepsy. METHODS: Women with epilepsy, treated with LTG in monotherapy and taking combination-type oral contraceptives, were randomized to treatment with placebo or a standard combination-type contraceptive pill. The dose-corrected trough plasma concentration of LTG and the ratio of N-2-glucuronide/unchanged LTG on urine after 21 days of concomitant placebo treatment was analyzed versus those after 21 days of concomitant treatment with the oral contraceptive pill. RESULTS: The mean dose-corrected LTG concentration after placebo treatment was 84%[95% confidence interval (CI), 45-134%] higher than after oral contraceptives, signifying an almost doubling of the concentration after cessation of oral contraceptives. Most of this increase took place within the first week after oral contraceptives were stopped. The N-2-glucuronide/LTG ratio in the urine was decreased by 31% (95% CI, -20-61%) when shifting from oral contraceptives to placebo. CONCLUSIONS: Cessation of oral contraceptives leads to an 84% increase in the concentration of LTG. In parallel, the excretion of the N-2-glucuronide was decreased, indicating that the changes are caused by altered LTG glucuronidation. The change in LTG concentrations was observed within 1 week of the shift of treatment, suggesting that induction and deinduction of LTG glucuronidation is faster than that seen for other metabolic pathways (e.g., cytochrome P450).

Pharmacokinetics of levetiracetam during pregnancy, delivery, in the neonatal period, and lactation.

PURPOSE: To study pharmacokinetics of levetiracetam (LEV) during pregnancy, delivery, lactation, and in the neonatal period. METHODS: Fourteen women with epilepsy receiving LEV treatment during pregnancy and lactation contributed with 15 pregnancies to this prospective study in which LEV concentrations in plasma and breast milk were determined. Trough maternal plasma samples were collected each trimester, and at baseline after delivery. Blood samples were obtained at delivery from mothers, from the umbilical cord, and from newborns during 2 days after delivery. LEV concentration was also determined in breast milk and in plasma collected from 11 of the mothers and their suckling infants after birth. RESULTS: The umbilical cord/maternal plasma concentration ratios ranged from 0.56-2.0 (mean 1.15, n=13). LEV plasma concentrations in the neonates declined with an estimated half-life of 18 h (n=13). The mean milk/maternal plasma concentration ratio was 1.05 (range, 0.78-1.55, n=11). The infant dose of LEV was estimated to 2.4 mg/kg/day, equivalent to 7.9% of the weight-normalized maternal dose. Plasma concentrations in breastfed were approximately 13% of the mother's plasma levels. Maternal plasma concentrations during third trimester were only 40% of baseline concentrations outside pregnancy (p<0.001, n=7) CONCLUSIONS: Our observations suggest considerable transplacental transport of LEV and fairly slow elimination in the neonate. Plasma concentrations of LEV in nursed infants are low despite an extensive transfer of LEV into breast milk. Pregnancy appears to enhance the elimination of LEV resulting in marked decline in plasma concentration, which suggests that therapeutic monitoring may be of value.

Determination of lamotrigine and its metabolites in human plasma by liquid chromatography-mass spectrometry.

A method based on electrospray ionization liquid chromatography-mass spectrometry was developed for the quantitative determination of lamotrigine and three of its reported metabolites, lamotrigine-2-N-glucuronide, lamotrigine-2-N-methyl, and lamotrigine-2-N-oxide in human blood plasma. The method utilized sample preparation by precipitation of proteins with acetonitrile, chromatographic separation on a reversed-phase system by gradient elution, and monitoring of the protonated molecular ions. Two internal standards, 3,5-diamino-6-(2-methoxyphenyl)-1,2,4-triazine and morphine-3-glucuronide-D3, were utilized to achieve precise quantification. The method validation comprised a demonstration of an agreement in the quantification of lamotrigine with that of a routine HPLC-UV method. The limits of detection were between 0.05 and 0.16 micromol/L. The method was employed for the measurement of clinical samples collected from 55 patients in steady-state prior to the dose intake (trough level). Lamotrigine and the 2-N-glucuronide were typically detected, while the N-methyl and N-oxide metabolites were detected only rarely. The median lamotrigine plasma level was 24.0 micromol/L (range, 4.3 to 64 micromol/L), the median 2-N-glucuronide level was 2.4 micromol/L (range, <0.05 to 24 micromol/L), and the median lamotrigine 2-N-glucuronide/lamotrigine ratio was 0.11 (range, <0.01 to 0.64). In conclusion, this liquid chromatographic-mass spectrometric method is suitable for simultaneous determination of lamotrigine and its metabolites in human plasma.

Carbamazepine protects against megencephaly and abnormal expression of BDNF and Nogo signaling components in the mceph/mceph mouse.

Carbamazepine (CBZ) is a commonly used antiepileptic drug known to block voltage-gated sodium channels. Infants exposed to CBZ in utero show reduced head circumference, for reasons unknown. We investigated CBZ's effect on neural growth in megencephaly (mceph/mceph) mice lacking functional Kv1.1. Mice fed with CBZ were assessed for brain structure size, seizure behavior and expression of markers for neuronal plasticity and rescue in brain. CBZ counteracted brain overgrowth and the increased size of neurons in the mceph/mceph mouse. These effects of CBZ occurred at doses that did not fully suppress epileptic behavior. Furthermore, CBZ normalized Bdnf mRNA levels and mRNA species encoding Nogo signaling pathway proteins. In conclusion, CBZ protects efficiently against abnormal growth and abnormal expression patterns of nerve growth signaling systems in the mceph/mceph brain. These observations and the effect of CBZ in utero suggest that CBZ treatment might be advantageous in some types of human idiopathic megalencephaly.