Relative proportions of serum carbamazepine and its pharmacologically active 10,11-epoxy derivative: effect of polytherapy and renal insufficiency.

BACKGROUND: The proposed action mechanism and pharmacological activity of carbamazepine (CBZ) and its major metabolite, carbamazepine-10,11-epoxide (CBZE), are the same. The aim of our study was the investigation of the effect of concomitant antiepileptic treatment and renal insufficiency on the relative proportions of serum CBZ and CBZE. METHODS: Serum trough steady-state CBZ and CBZE concentrations were determined by high-performance liquid chromatography (HPLC) in 140 epileptic patients treated with CBZ in monotherapy (n=100) and polytherapy with phenytoin, phenobarbital and valproate (n=40). The levels of CBZ were also determined using the Dade Behring enzyme multiplied immunoassay technique (EMIT). The glomerular filtration rate (GFR) was estimated from serum cystatin C using the Dade Behring nephelometric immunoassay. RESULTS: The CBZE/CBZ and CBZ+CBZE/CBZEMIT ratios were significantly increased in 7 cases (3 in monotherapy and 4 in polytherapy) with GFR<60 mL/min/1.73m2 in relation to the patients treated in monotherapy or polytherapy having normal or mildly decreased renal function (p<0.001). CONCLUSIONS: In patients with moderate to severe renal insufficiency the relative proportion of CBZE with respect to the parent drug is significantly increased. In these cases, the CBZ concentrations obtained using the EMIT, or other immunoassays having low CBZE cross-reactivity, may have an inadequate diagnostic efficiency.

Renal tubular dysfunction in schizophrenic patients treated with antipsychotic drugs.

Several factors have been considered in relation to the free radical formation in schizophrenia, such as the disease itself, drug treatment and smoking. Several chemicals and drugs may cause damage to the renal tubules by different subcellular mechanisms including oxidative stress, and the aim of our study was the investigation of tubular dysfunction in schizophrenic patients. The urinary excretion of beta-N-acetylhexosaminidase (Hex) and its isoenzymes Hex A and Hex B, alpha1-microglobulin, albumin, total proteins and fractionated porphyrins were determined in 45 schizophrenic patients treated with first- and second-generation antipsychotics. In 7 patients, an increase in proteinuria of tubular origin was found, and in one as a result of mixed glomerular/tubular origin. The group of patients had a significantly higher level of excretion than the control group (n = 54) of total Hex (p < 0.001), Hex A (p < 0.05), Hex B (p < 0.001) and the relative proportion of this isoenzyme (p < 0.001). In some cases with normal levels of total Hex and urinary alpha1-microglobulin, the proportion of Hex B was already increased. Significant correlations were found for total Hex and its isoenzymes with alpha1-microglobulin (p < 0.001). Also, the porphyrins had significant correlations with total Hex (p < 0.001), Hex A (p < 0.05), Hex B (p < 0.005) and alpha1-microglobulin (p < 0.001). In the group of patients studied, it was possible to reveal early tubular cell damage (affected structural integrity) with increased excretion of Hex B, possibly mediated by free radicals, previous to the decrease in tubular reabsorption of proteins with low molecular mass filtered by the glomerulus (affected functional integrity).