Diagnostic efficiency of truncated area under the curve from 0 to 2 h (AUC0₋2) of mycophenolic acid in kidney transplant recipients receiving mycophenolate mofetil and concomitant tacrolimus.

BACKGROUND: Recently, the use of the truncated area under the curve from 0 to 2 h (AUC(0-2)) of mycophenolic acid (MPA) has been proposed for therapeutic monitoring in liver transplant recipients. The aim of our study was the evaluation of the clinical usefulness of truncated AUC(0-2) in kidney transplant patients. METHODS: Plasma MPA was measured in samples taken before the morning dose of mycophenolate mofetil, and one-half and 2 h post-dose, completing 63 MPA concentration-time profiles from 40 adult kidney transplant recipients. The AUC from 0 to 12 h (AUC(0-12)) was calculated using the validated algorithm of Pawinski et al. The truncated AUC(0-2) was calculated using the linear trapezoidal rule, and extrapolated to 0-12 h (trapezoidal extrapolated AUC(0-12)) as previously described. RESULTS: Algorithm calculated and trapezoidal extrapolated AUC(0-12) values showed high correlation (r=0.995) and acceptable dispersion (ma68=0.71 µg·h/mL), median prediction error (6.6%) and median absolute prediction error (12.6%). The truncated AUC(0-2) had acceptable diagnostic efficiency (87%) in the classification of subtherapeutic, therapeutic or supratherapeutic values with respect to AUC(0-12). However, due to the high inter-individual variation of the drug absorption-rate, the dispersion between both pharmacokinetic variables (ma68=6.9 µg·h/mL) was unacceptable. CONCLUSIONS: The substantial dispersion between truncated AUC(0-2) and AUC(0-12) values may be a serious objection for the routine use of MPA AUC(0-2) in clinical practice.

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).

Relation of blood platelet count during carbamazepine and oxcarbazepine treatment with daily dose, and serum concentrations of carbamazepine, carbamazepine-10, 11-epoxide, and 10-hydroxycarbazepine.

BACKGROUND: Carbamazepine (CBZ) occasionally causes haematological disorders such as thrombocytopenia, and recently a case of oxcarbazepine (OXCBZ)-induced thrombocytopenia has been described. The aim of our study was blood platelet count determination in epileptic patients treated with CBZ and OXCBZ, and its relationship with the dose and serum levels of these drugs and its metabolites. METHODS: The serum levels of CBZ and its epoxide, and the pharmacologically active monohydroxy derivative of OXCBZ were determined in 137 patients treated with CBZ, and 60 patients treated with OXCBZ. The platelet count, mean platelet volume, and platelet size distribution width were also determined. RESULTS: The difference between the platelet counts of the patient groups treated with CBZ and OXCBZ was not significant. No significant correlations between the platelet count and serum levels of the administered antiepileptic drugs and their metabolites were found. However, significant negative correlations between the platelet count and the daily doses of CBZ and OXCBZ were obtained (p<0.01). In 5 cases (4 treated with CBZ and 1 with OXCBZ) the platelet count was <150 x 10(9)/l. CONCLUSIONS: In accordance with the mean platelet volume and platelet distribution width, the thrombocytopenia observed in some of the patients studied was due to a hyper-destruction of peripheral blood platelets. However, the results obtained suggest that the mechanism of CBZ or OXCBZ-induced thrombocytopenia is not due to a direct toxicity of these drugs or their major metabolites on the circulating platelets. Although, the patients treated with OXCBZ shown a lower prevalence for thrombocytopenia (1.7%) than those treated with CBZ (2.9%), the routine platelet count monitoring in patients treated with both drugs may be recommended.

Possible induction of cholinesterase in epileptic patients treated with anticonvulsant drugs: relationship with lipoprotein levels.

The effect of enzyme-inducing anticonvulsant drugs on the serum concentrations of lipoproteins has been widely studied. However, there is little agreement between the results with regard to the possible development of a lipoprotein profile related to an increased or decreased cardiovascular risk. It has been suggested that cholinesterase (ChE) could be induced by these drugs, something of undeniable interest as ChE appears to have a relation to the metabolism of lipoproteins. The serum activity of ChE was determined in a group of 90 adult epileptic patients (56 male and 34 female) treated with phenobarbital, phenytoin, and carbamazepine. The liver enzyme induction produced by these drugs was then evaluated by determining serum gamma-glutamyltranspherase activity and urinary excretion of D-glucaric acid. A significant increase of serum ChE (p < 0.005) was found in the group of patients compared to a control group (n = 49) with a similar distribution for age and sex. A significant correlation was found for both male and female patients between ChE and concentrations of triglycerides, phospholipids, cholesterol, low-density lipoprotein (LDL) phospholipids, LDL-cholesterol, and apolipoprotein B (p < 0.01). Similarly, in female patients, ChE had a significant correlation with the total cholesterol/high-density lipoprotein (HDL) cholesterol and LDL-cholesterol/HDL-cholesterol ratios (p < 0.01). The ChE/HDL-cholesterol relationship, which has been proposed as a marker for cardiovascular risk, presented significant correlations with the total cholesterol/HDL-cholesterol and LDL-cholesterol/HDL-cholesterol ratios in patients of both sexes (p < 0.001). In the case of epileptic patients treated with enzyme-inducing anticonvulsant drugs, there may be an association between the possible induction of ChE and the metabolism of lipoproteins containing apolipoprotein B.

Activation of serum aminotransferases by pyridoxal-5' -phosphate in epileptic patients treated with anticonvulsant drugs.

OBJECTIVES: Significant decreases in the serum concentration of pyridoxal-5' -phosphate (PLP) have been described in epileptic patients treated with anticonvulsant drugs. This would be expected to lead to a decrease in the sensitivity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) for the detection of hepatocellular damage in these patients if optimized methods with coenzyme supplementation are not used. The aim of our study was to evaluate this hypothesis. DESIGN AND METHODS: The serum activities of AST and ALT (with and without the addition of PLP) were determined in a group of 90 adult epileptic patients (56 male, 34 female) undergoing chronic treatment polytherapy with phenobarbital, phenytoin, carbamazepine, and valproic acid. As a control group, 49 clinically healthy individuals were studied with a similar distribution for age and sex. RESULTS: Supplementation with PLP produced an activation of AST and ALT in both the control and patient groups with a highly significant correlation between the enzyme activities with and without the addition of PLP (r > or = 0.956, P < 0.001). The differences between the control and patient groups for the PLP activation of both aminotransferases were not clinically significant. The increases in AST (9%) and ALT (28%) in the patient group compared to the control group were lower than those found for alcohol dehydrogenase (ADH, 82%) and alpha-glutathione S-transferase (alphaGST, 76%). CONCLUSIONS: It does not appear that in the epileptic patients studied the in vitro addition of PLP increased the diagnostic sensitivity of AST and ALT for hepatocellular injury. The lower responses of both aminotransferases to the action of anticonvulsant drugs in relation to other cytosolic enzymes may be due to the preferred periportal localization of AST and ALT in the hepatic lobe.

Assessment of copper status in epileptic patients treated with anticonvulsant drugs by measuring the specific oxidase activity of ceruloplasmin.

Significant increases in serum levels and decreases in hair copper levels have been previously described in epileptic patients treated with anticonvulsant drugs. A condition not directly related to copper nutriture, such as chronic treatment with these drugs, could increase the serum concentrations of copper and ceruloplasmin and would mask a possible copper deficiency produced by drug-increased biliary copper excretion. Serum immunoreactive ceruloplasmin concentration and its oxidase activity were determined in 90 adult epileptic patients treated with phenobarbital (n=60), phenytoin (n=70), carbamazepine (n=33) and valproic acid (n=8). The levels of ceruloplasmin and oxidase activity were significantly higher (P<0.001) than in an age and gender-matched control group (n=49). The significant correlations (P<0.01) between ceruloplasmin and the urinary excretion of D-glucaric acid, serum gamma-glutamyltransferase (GGT) and drug score in the patients group, would suggest that phenobarbital-type enzyme-inducing agents may increase the hepatic synthesis of ceruloplasmin. In 11 patients with a beta-globulin migrating GGT isoform (GGT3), a sensitive marker of cholestasis, the levels of ceruloplasmin, oxidase activity and total GGT activity were significantly higher (P<0.05) than in the group of 79 patients without the GGT3 isoform; consequently, in some cases a drug-induced cholestasis may also contribute to the increase of serum copper and ceruloplasmin. The values obtained for the specific oxidase activity of ceruloplasmin (activity per unit mass of enzyme protein) suggest that in the most of the cases, chronic administration of phenobarbital, phenytoin, carbamazepine or valproic acid, does not produce marginal or moderate copper deficiency.

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.

Phenytoin immunoassay measurements in serum samples from patients with renal insufficiency: comparison with high-performance liquid chromatography.

The debate continues regarding the possible interference of phenytoin metabolites in phenytoin immunoassays, and its clinical importance for patients with renal failure. The aim of this study was to compare the results obtained using the Abbott fluorescence polarization immunoassay (FPIA), Dade enzyme-multiplied immunoassay technique (EMIT), and high-performance liquid chromatography (HPLC) to establish the significance of the differences in conditions of renal failure. Thirty-six adult patients who had been treated with phenytoin and whose renal function ranged from normal to severely impaired were chosen for this study. In accordance with previously established validation criteria for analytical methods for the determination of drugs, a 15% bias from the HPLC phenytoin values was considered an acceptable limit. The mean (+/-SEM) glomerular filtration rate (GFR) of the patients was 37.5+/-4.6 mL/min (range = 10-102 mL/min). The mean values found using FPIA (10.8+/-1.2 microg/mL) and EMIT (10.8+/-1.3 microg/mL) presented acceptable deviations with respect to HPLC (10.5+/-1.2 microg/mL), and a high correlation was found among the results (N = 36) of the different methods (r > or = 0.987, P < 0.001). An FPIA deviation above the 15% bias limit with respect to HPLC was found only in two cases with very low serum phenytoin concentrations and low GFR values (< 20 mL/min), although it does not appear to be important in terms of adjusting drug dosage. According to our data, FPIA and EMIT gave accurate results for total phenytoin in serum samples from patients with renal failure.

Effect of antiepileptic drugs on the urinary excretion of porphyrins in non-porphyric subjects.

The action of some anticonvulsant drugs as the causal agents of attacks of acute porphyria has been widely documented in the literature. However, little attention has been paid to the effect of these drugs on the urinary excretion of porphyrins in non-porphyric subjects. In a sample of 82 epileptic patients treated with phenobarbital (n = 54), phenytoin (n = 64), carbamazepine (n = 33), and valproate (n = 8), the daily doses were expressed according to a drug score that would reflect the capacity of these drugs as enzymatic inducers when administered in polytherapy. A significantly increased urinary excretion of D-glucaric acid (DGA) and porphyrins was found in this group of patients (P<0.001), with coproporphyrin being the major fraction in all cases (>60%). Urinary DGA had a highly significant correlation with the drug score (r = 0.783, P<0.001); however, no significant correlations were found between the urinary porphyrins and DGA (r = 0.005) or the drug score (r = 0.053). Neither was any significant relationship found between the urinary porphyrins and the serum activity of 5'-nucleotidase (r = 0.066) or the presence of a cholestasis objectivized through the presence of the isoform of gamma-glutamyltransferase with beta-globulins electrophoretic mobility. However, in a group of 10 patients a significant correlation was found between the urinary excretion of porphyrins and beta-N-acetylhexosaminidase (r = 0.790, P<0.01). Therefore, it does not appear that the liver enzyme induction, or even a subclinical cholestasis, produced by the antiepileptic drugs administered to these patients may serve to explain the increase in the urinary excretion of porphyrins. A possible renal origin is proposed for the increase of urinary porphyrins in these cases.