Pharmacokinetic study of carbamazepine and its carbamazepine 10,11-epoxide metabolite in a group of female epileptic patients under chronic treatment.

BACKGROUND: Although epileptic crises are equally frequent in women and men, several factors cause female epileptics to present a series of gender-specific problems. To date, few studies have been published on the kinetics of carbamazepine (CBZ) and carbamazepine 10,11-epoxide (CBZ-E) active metabolite in a Mexican population, and no information for epileptic women of reproductive age is available. The aim of the present work was to study the pharmacokinetic behavior of this group of women during steady state. METHODS: Fourteen epileptic women under chronic treatment receiving only the anticonvulsant CBZ to control their crises were studied. A blood sample was taken before breakfast, before the morning dose of 200 mg, and after the dose at 1, 2, 3, 4, 5, and 8 h. Serum was separated by centrifugation at 1,350 x g. Serum concentrations of carbamazepine (CBZ) and of the metabolite carbamazepine 10,11-epoxide (CBZ-E) were measured by HPLC. Pharmacokinetic parameters were calculated by statistical moment method after obtaining serum concentrations. RESULTS: Maximum time (T(max)) for CBZ was reached at 2.72+/-0.71 h and for CBZ-E, it was 3.60+/-0.79 h. C(max) for CBZ was 7.30+/-2.30 microg/mL, while C(min) for CBZ was 6.30+/-2.49. Maximum serum values for CBZ-E were 1.01+/-0.57, equivalent to 13.80% of CBZ; t(12) value for CBZ and CBZ-E was 18.20 and 16.10 h, respectively. AUC values for CBZ and metabolite were 70.33+/-17.10 microg/L/h and 9.20+/-2.50 microg/L/h, respectively. CBZ and CBZ-E clearance did not show differences and were 0.37 mL/kg/min and 0.40 mL/kg/min, respectively. Extraction index for serum concentrations of CBZ and CBZ-E AUC(CBZ)/AUC(CBZ-E) was 0.13; positive correlation was observed between serum concentrations of CBZ and E-CBZ, with r=0.94. CONCLUSIONS: The schedule we suggest for therapeutic monitoring of serum concentrations of CBZ in chronic treatments is 3 h for maximum peak concentration of C(max) after dose administration and for minimum peak concentration, C(min) prior to subsequent administration of the dose.

Amikacin alters auditory brainstem conduction time in newborns.

The purpose of this paper was to describe whether there are some relationships between amikacin serum levels and central conduction time in brainstem auditory evoked potentials (BAEP) within therapeutic range levels in newborns as index of drug toxicity in brainstem auditory centers in neonatally exposed infants. We performed a cross-sectional study to compare BAEP from 35 infants under amikacin administration and 24 control infants; both examinations were blinded to investigators. Bivariate and partial correlations were calculated between amikacin and BAEP measurements in treated infants. Amikacin determinations were within therapeutic levels. No clinical alterations in BAEP were found and no differences between amikacin-treated and control infants were found. Significant positive Pearson correlation between latency of I-III interwaves interval and amikacin Cmin serum levels was found and was present when calculations were controlled by partial correlations for gestational age at birth and Apgar score at 5 min. The findings suggest that increased amikacin levels in newborns are related to increased latencies in I-III interwave interval in infants, which may be an early index of brainstem effects of subclinical neurotoxicity of amikacin.

Effects of prenatal exposure to carbamazepine on brainstem auditory evoked potentials in infants of epileptic mothers.

The purpose of this study was to determine if there are any correlations between carbamazepine serum levels of epileptic mothers during pregnancy and the brainstem auditory evoked potentials in their infants as an index of drug neurotoxicity in newborns exposed prenatally. We included 20 epileptic mothers with carbamazepine medication and their 20 otherwise healthy infants. The study was conducted from September 1, 1993, to December 15, 1999. Serum carbamazepine determinations were performed monthly by enzymatic immunoanalysis in the mothers, and the averages for each trimester during pregnancy were calculated. Brainstem auditory evoked potentials were performed at 10.2 +/- 4.6 weeks of postnatal life. Pearson's correlations were calculated between carbamazepine serum levels during pregnancy and waves and interwave intervals of brainstem auditory evoked potentials. Both examinations were performed without knowledge of the results of the other investigations. No alterations in the infants' brainstem auditory evoked potentials were evident, and carbamazepine determinations were within therapeutic levels. Significant Pearson's correlations between latencies of waves III and V and third trimester of carbamazepine serum concentration levels and I-V interwave intervals to third-trimester minimum serum levels of carbamazepine were found. The findings suggest that the higher carbamazepine levels in mothers are related to increased latencies in waves III and V and I-V interwave intervals in infants subclinically, which could be an early index of fetal neurotoxicity.

Comparación del análisis inmunoenzimático y la cromatografía de líquidos de alta eficiencia (EMIT y HPLC) para la medición de carbamacepina en muestras séricas / Comparison of enzyme immunoassay and high-performance liquid chromatography determination of carbamazepine in human serum

Se analizaron 40 muestras de suero de pacientes tratados con carbamacepina por inmunoanálisis enzimático (EMIT) y cromatografía de líquidos de alta eficiencia (HPLC) y se compararon los resultados. El método cromatográfico incluye la extracción de la carbamacepina con cloruro de metileno y su separación cromatográfica en una columna Nova Pak C18 usando una mezcla de acetonitrilo al 25 por ciento en agua pH 5.6. La detección se hizo en un detector de absorbancia a 215 nm. La correlación entre estos dos métodos fue de 0.93. Las bandas de confianza para la predicción de HPLC en función de EMIT calculadas mediante el criterio de Working-Hotelling, mostraron un error máximo de 1.1, 0.5 y 1.6 µg/ml en el rango bajo, medio y alto respectivamente con una probabilidad 0.05. La ecuación que expresa el comportamiento de la medición de carbamacepina por HPLC en función del EMIT es: HPLC = 0.824 x EMIT + 0.777 Posteriormente, se usó el método cromatográfico para determinar los niveles séricos predosis de carbamacepina y 10,11-epoxi-carbamacepina en 5 pacientes epilépticas que recibieron una dosis oral de 200 mg de carbamacepina cada 8 horas como único anticonvulsivante para el control de sus crisis.