Differential but infrequent alterations of hepatic enzyme levels and thyroid hormone levels by anticonvulsant drugs.

OBJECTIVE: To assess the differential effects of antiepileptic drugs (AEDs) on hepatic enzyme and thyroid hormone levels and to assess the frequency and degree of these alterations. STUDY DESIGN: Retrospective analysis of hepatic enzyme (serum aspartate aminotransferase and alanine aminotransferase) and thyroid hormone (thyroxine, T uptake; and free thyroxine index) levels obtained during a 10-year period in a large unselected outpatient population of patients with epilepsy. PATIENTS: Unselected (for age, sex, race, type of epilepsy, or degree of control) epileptic subjects (n = 642 for determination of hepatic enzyme levels and n = 317 for determination of thyroid hormone levels) attending the largest outpatient epilepsy center in the Midwest. Infants (younger than 1 year) and those receiving more than two AEDs were excluded. OUTCOME MEASURE: Hepatic enzyme and thyroid hormone level alterations vis-à-vis the type of AED, serum AED levels, and monotherapy vs bitherapy. RESULTS: Aspartate aminotransferase level alterations were mainly due to valproate or phenobarbital, and alanine aminotransferase alterations were due to phenytoin. Significant enzyme level elevations were infrequent (2% [14/642] of patients), mild, usually associated with bitherapy, transient, and confined to aspartate aminotransferase level. Persistent elevations of both aspartate aminotransferase and alanine aminotransferase levels occurred in only one patient, and he had underlying liver disease. Phenytoin was most and phenobarbital least likely to influence the thyroid indexes. Although bitherapy was more likely to produce biochemical alterations of thyroid hormone levels compared with monotherapy, clinically significant thyroid hormone level alterations were seen in only one of 317 patients, and this patient was known to have hypothyroidism. CONCLUSIONS: Antiepileptic drugs affect hepatic enzyme and thyroid hormone levels differentially, and bitherapy alters them more than monotherapy does. However, alterations are mostly mild and clinically insignificant and do not justify routine testing, except in those known to have a coexisting hepatic or thyroid abnormality, those who develop symptoms of hepatic or thyroid involvement while receiving AEDs, and perhaps those receiving bitherapy with high serum AED levels.

Derivation and evaluation of an equation for prediction of free carbamazepine concentrations in patients comedicated with valproic acid.

The relationship between free carbamazepine fraction (F-CBZ-F) and valproic acid (VPA) was studied in 50 outpatients coming for regular visits to our clinic throughout the day, and was compared with 50 patients without VPA comedication under similar conditions. F-CBZ-F was found to be significantly (t = 3.5, df = 98, p less than 0.001) higher for VPA comedicated patients (0.291 +/- 0.024) when compared with patients without VPA (0.247 +/- 0.016). Linear regression analysis for total plasma VPA concentration versus F-CBZ-F gave the equation: F-CBZ-F = 0.247 + 0.00062 (VPA); n = 50, r = 0.697, p less than 0.001, indicating unreliable prediction of F-CBZ-F from VPA concentration. Substituting the parameter F-CBZ-F by its equivalent (F-CBZ/CBZ) yielded the equation F-CBZ = [0.247 + 0.00062 (VPA)] CBZ. The predictive power of this equation was evaluated by the comparison of obtained and predicted F-CBZ concentrations. An excellent agreement (n = 50, r = 0.981, p less than 0.001) was obtained. Although the empirically derived constants of the equation are not unique and may vary depending on the conditions of different methodologies, the fundamental relationship has been established and can be used to reliably predict F-CBZ concentration from plasma VPA and CBZ concentration.

Derivation and evaluation of an equation for prediction of free phenytoin concentration in patients co-medicated with valproic acid.

The relationship between free phenytoin fraction (F-PHT-F) and valproic acid (VPA) was studied under two conditions: (a) in serum samples from 43 institutionalized patients (212 serial data points) at plateau steady state, and (b) in plasma samples from 50 outpatients coming for regular visits to our clinic throughout the day. Results for both groups led to identical linear regression equations relating F-PHT-F to VPA: F-PHT-F = 0.095 + 0.001 (VPA). Nevertheless, as expected, the resulting equation gave an unreliable prediction of F-PHT-F due to a variable physiological matrix. Substituting the parameter F-PHT-F by its equivalent (F-PHT/PHT) gave the equation F-PHT = [0.095 + 0.001 (VPA)] PHT. The predictive power of this equation was evaluated by the comparison of obtained and predicted F-PHT concentrations. For the combined patient group (n = 93), an excellent agreement (r = 0.972 and F = 999.9; p less than 0.001) was obtained. Although the empirically derived constants of the equation are not unique and may vary depending on the conditions of different methodologies, the fundamental relationship has been established and can be used to reliably predict F-PHT concentration from plasma VPA and PHT concentrations.

Chronic antiepileptic drug therapy: classification by medication regimen and incidence of decreases in serum thyroxine and free thyroxine index.

Results are described on the association of decreased serum total thyroxine (T4) and free thyroxine index (FTI) with antiepileptic drug therapy in a group of randomly selected chronically medicated outpatients (n = 291). For monotherapy subgroups (n = 164), the highest incidence (T4, 23.9%; FTI, 25.4%) of below normal values occurred in patients medicated with carbamazepine (CBZ), followed by phenytoin [(PHT) T4, 13.2%; FTI, 7.9%], and phenobarbital [(PB) (T4, 3.4%; FTI, 0%]. No T4 and FTI values below normal were detected in any patients (n = 30) on chronic valproic acid (VPA) monotherapy. For CBZ monotherapy (n = 67), women (n = 37) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 30). Therefore, the order of decreasing T4 and FTI effect was as follows: CBZ (women) greater than CBZ (men) greater than PHT greater than PB greater than VPA. For polytherapy subgroups (n = 127), the highest incidence (T4, 51.9%; FTI, 48.1%) was found in patients medicated with PHT and CBZ, followed by PHT and VPA (T4, 37.0%; FTI, 23.9%), and PHT and PB (T4, 17.2%; FTI, 10.3%). For PHT and CBZ poly-therapy (n = 52), women (n = 21) had a higher frequency of below normal values of T4 (p less than 0.05) and FTI (p less than 0.001) than men (n = 31). The magnitude of the decreasing T4 and FTI effect was greater for polytherapy subgroups (versus monotherapy subgroups) and in order as follows: PHT + CBZ (women) greater than PHT + CB (men) greater than PHT + VPA greater than PHT + PB.(ABSTRACT TRUNCATED AT 250 WORDS)

Dual effects of carbamazepine-phenytoin interaction.

By intrapatient comparison at constant phenytoin (PHT) dose, the effect of increased carbamazepine (CBZ) dose was studied in 32 epileptic outpatients treated with a combination of PHT and CBZ. The mean PHT plasma concentration, as well as the concentration/dose ratio for PHT, became significantly higher secondary to increased doses of CBZ (14.1 +/- 3.5 vs. 19.3 +/- 3.6 micrograms/ml and 2.8 +/- 1.0 vs. 3.9 +/- 1.4 micrograms/ml plasma per milligram/kilogram daily dose, respectively; p less than 0.001). Concomitantly, in spite of CBZ dose higher by 17.6%, the CBZ concentration increased by only 6.4%, and the CBZ concentration/dose ratio actually decreased by 10%. In contrast, by intrapatient comparison at constant CBZ dose, the effect of reduced PHT dose on CBZ was studied in 22 patients. The mean CBZ plasma concentration as well as the concentration/dose ratio for CBZ appeared significantly higher, with a concomitant reduction of PHT (6.7 +/- 1.6 vs. 8.6 +/- 1.6 micrograms/ml and 0.37 +/- 0.1 vs. 0.49 +/- 0.2 micrograms/ml plasma per milligram/kilogram daily dose, respectively; p less than 0.001). This simultaneous dual effect--inhibition of PHT metabolism by CBZ and induction of CBZ metabolism by PHT--can result in PHT intoxication along with a fall in CBZ plasma concentration to a subtherapeutic range. This effect may be avoided or reduced if the PHT concentration is adjusted to approximately 13 micrograms/ml before CBZ is added or increased.

Clinically significant danazol-carbamazepine interaction.

In six patients with epilepsy and fibrocystic breast disease the concentration in serum of antiepileptic drugs was obtained before, during, and after danazol therapy. Carbamazepine serum levels increased almost twofold in the presence of danazol. Thus, interaction between carbamazepine and danazol producing acute carbamazepine toxicity is clinically significant. If these drugs are administered concurrently, an awareness of the potential for this drug-drug interaction along with monitoring of carbamazepine levels is required for optimal patient care.

Role of octanoic and decanoic acids in the control of seizures.

Octanoic and decanoic acid, the major constituents of the Medium Chain Triglyceride (MCT) Emulsion diet, have been detected in appreciable quantities in the peripheral blood of children with intractable seizures treated with the MCT diet. Serum concentrations of these acids as well as beta hydroxybutyrate and acetoacetate rose as the diet was introduced and on full diet showed pronounced diurnal variation and low concentrations in the morning. No correlation between octanoic and decanoic acid concentrations and control of seizures was established, but further studies with octanoic and decanoic acid using animal models are necessary to assess the role of these acids and of control of seizures.

The medium chain triglyceride diet and intractable epilepsy.

Fifty children with drug resistant epilepsy were treated with the Medium Chain Triglyceride (MCT) Emulsion diet. Eight achieved complete control of seizures (four without anticonvulsant drugs), and with the addition of anticonvulsants four had seizures reduced in frequency by 90% and 10 by 50-90%. The best results were obtained with astatic myoclonic and absence seizures, but control of seizures was improved in four children with tonic-clonic and three with complex partial seizures. Food given at the same time as MCT helped to reduce side effects, and an extra dose of MCT before bedtime improved control of nocturnal seizures.

Chronic valproic acid and coantiepileptic drug therapy and incidence of increases in serum liver enzymes.

Results are described on the association of increased serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) activities with valproic acid (VPA) and coantiepileptic drug therapy in a group (n = 126) of randomly selected chronically medicated out-patients. The highest incidence (SGOT, 28.3%; SGPT, 26.1%) of elevations occurred in patients comedicated with VPA-phenobarbital (PB)-phenytoin (PHT) combinations, followed by those in the VPA-PB group (SGOT, 19.5%; SGPT, 7.3%). No SGPT elevations were detected in any patients (n = 40) on chronic VPA monotherapy, while SGOT was marginally elevated in 20% of the cases. Considering the total sample (n = 126), SGOT activities were found to be linearly and directly correlated with VPA plasma concentration (n = 126, r = 0.228, p less than 0.01), PB concentration (n = 86, r = 0.352, p less than 0.01), PHT concentration (n = 45, r = 0.336, p less than 0.01), sum of VPA-PB concentrations (n = 86, r = 0.440, p less than 0.001), and sum of VPA-PB-PHT concentrations (n = 45, r = 0.481, p less than 0.001). The corresponding correlations for SGPT activities were similar, except that no correlation was observed in the case of VPA monotherapy. Student's t tests for equality of means showed that the subgroup with abnormal enzyme activities had a significantly higher mean plasma concentration for PB, PHT, sum of VPA-PB, and sum of VPA-PB-PHT when compared with normal enzyme subgroup patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic valproic acid therapy and incidence of increases in venous plasma ammonia.

Results are described on the association of elevated ammonia (NH3) with valproic acid (VPA) therapy in a large group (n = 157) of randomly selected, chronically medicated (greater than 2 years) outpatients. The highest incidence (45.5%) of elevations occurred in patients comedicated with VPA-phenobarbital (PB)-phenytoin (PHT) combinations, followed by VPA-PB (33.3%) and VPA-PHT (15.4%). No NH3 elevations were detected in all patients (n = 38) on chronic VPA monotherapy. Considering the total sample (n = 157), NH3 concentrations were found to be linearly and directly correlated with VPA plasma concentration (n = 125, r = 0.249, p less than 0.001), PB concentration (n = 86, r = 0.411, p less than 0.001), sum of VPA-PB concentration (n = 60, r = 0.721, p less than 0.001), and sum of VPA-PB-PHT concentration (n = 33, r = 0.802, p less than 0.001). When patients in the subgroups (n = 73) that included all the patients with elevated NH3 were separated into one group (n = 47) with normal NH3 (less than or equal to 0.70 micrograms/ml) and one group (n = 26) with elevated NH3 (greater than or equal to 0.71 micrograms/ml), Student's t tests for equality of means showed that the group with elevated NH3 had a significantly higher mean plasma concentration for VPA, PB, sum of VPA-PB, and sum of VPA-PB-PHT (all at p less than 0.001) when compared with the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of phenothiazines on serum antiepileptic drug concentrations in psychiatric patients with seizure disorder.

The intrapatient effect of starting (group A, n = 16), increasing (group B, n = 19), decreasing (group C, n = 23), and discontinuing (group D, n = 34) the phenothiazines (PHZs) thioridazine, chlorpromazine, or mesoridazine on serum phenytoin (PHT), phenobarbital (PB), and primidone (PRI) was studied at a constant antiepileptic drug regimen and between two consecutive steady-state concentration determinations in 92 institutionalized epileptic patients with psychiatric disorders. For PHZ initiation or dosage increase (groups A and B), serum PHT and PHT concentration-to-dose ratio (C/D) decreased by 44 (p less than 0.001) and 41.6% (p less than 0.001) in group A, and 32.9 (p less than 0.001) and 35.3% (p less than 0.005) in group B, respectively. For PHZ dosage decrease or discontinuation (groups C and D), serum PHT and C/D ratio increased by 54.8 (p less than 0.001) and 51.3% (p less than 0.01) in group C, and 71.2 (p less than 0.001) and 69.2% (p less than 0.001) in group D, respectively. The changes for PB were in the same direction, although to a lesser extent. No statistically significant differences were noted for PRI. For groups A and B, the clinical trend was for increase in number of seizures when PHZs were started or dosage increased. For groups C and D, a clear trend for PHT intoxication was evident when PHZ dosages were decreased or discontinued.

Carbamazepine-phenytoin interaction: elevation of plasma phenytoin concentrations due to carbamazepine comedication.

By intrapatient comparison at constant phenytoin (PHT) dose, the effect of carbamazepine (CBZ) comedication on PHT was studied in a group of 24 epileptic outpatients. In half of the patients with steady-state PHT plasma concentration, a significant increase of this concentration was noted after CBZ was added to their regimen. Twenty percent showed clinical manifestations of acute drug toxicity initially thought to be CBZ related. The mean PHT plasma concentration for the 12 patients (22.7 +/- 5.64 micrograms/ml) as well as concentration/dose ratio for PHT (4.61 +/- 1.65 micrograms/ml plasma per mg/kg/day dose) was significantly higher (p less than 0.001) with concomitant administration of CBZ than when PHT was given alone: PHT concentration, 12.54 +/- 3.93 micrograms/ml and PHT concentration/dose ratio, 2.52 +/- 0.78 micrograms/ml plasma per mg/kg/day dose. Those patients with higher PHT plasma concentrations seem to be at higher risk of PHT toxicity due to CBZ comedication.

Elevation of beta-glucuronidase activity in medicated patients with epilepsy.

Elevations of serum beta-glucuronidase (GRS) enzyme activity can occur under a variety of pathological conditions. Using phenolphthalein glucuronic acid as the substrate, 158 epileptic patients were randomly screened for GRS. GRS was distinctly elevated (65.9 +/- 30.0 micrograms phenolphthalein/ml serum) in patients, compared with the normal group (27.0 +/- 10.0). No difference in GRS levels were found when seizure-free (greater than 1 year) patients (n = 61; GRS, 62.6 +/- 32.7 micrograms) were compared with patients who had seizure episodes within 1 week (n = 26; GRS, 73.2 +/- 24.9 micrograms), and there were no differences when intermediate groups were examined. GRS elevations were found to be linearly and directly correlated with free phenytoin ultrafiltrate levels (n = 35, r = 0.7692, p less than 0.0001) when patients were co-medicated with valproic acid, with serum phenobarbital levels (n = 58, r = 0.5361, p less than 0.05), with serum valproic acid levels (n = 43, r = 0.3173, p less than 0.05), and with the sum of serum phenobarbital and valproic acid levels (n = 16, r = 0.8657, p less than 0.0001). The findings indicate that GRS elevations are probably due to anticonvulsant medications rather than to the frequency of seizures. There is no evidence that GRS determinations can be used for the diagnosis or prognosis of patients with epilepsy.

Therapeutic serum concentrations of primidone and its metabolites, phenobarbital and phenylethylmalonamide in epileptic dogs.

Fifteen dogs with idiopathic epilepsy were included in a 9-month clinical trial to determine the therapeutic serum concentrations of primidone and its active metabolites, phenobarbital and phenylethylmalonamide. Dogs with a seizure frequency greater than 1/mo or with a record of multiple seizures greater than 1/day were chosen for the study. Each dog was given primidone 3 times daily at dosages intended to maximize seizure control and to minimize undesired side effects. Maintenance period blood samples were taken from fasted dogs 7 hours after dosing in the 3rd, 5th, 7th, and 9th months of the trial to determine therapeutic serum concentrations of primidone and its metabolites. Two blood samples also were taken from all dogs 7 hours after dosing, during an enforced drowsy period, to establish upper limits of desirable serum concentrations of the drug. Seizure frequencies during the trial were controlled in 13 dogs, 7 of which had no seizures during the 9-month trial. The mean percentage reduction in seizure frequency from pretrial frequency was 85%. Two dogs appeared refractory to primidone therapy. Serum phenobarbital was the best metabolite of primidone to use to assess therapeutic serum concentrations. The therapeutic antiepileptic serum concentration of phenobarbital was found to be between 25 and 40 micrograms/ml of serum. Serum phenobarbital concentrations greater than 40 micrograms/ml resulted in side effects in most dogs.

Monitoring octanoic and decanoic acids in plasma from children with intractable epilepsy treated with medium-chain triglyceride diet.

We describe a procedure for gas-chromatographic determination of n-octanoic and n-decanoic acids in 100 microL of plasma from children with intractable epilepsy treated with medium-chain triglyceride (MCT) diet. With n-nonanoic acid as the internal standard, the extraction efficiencies for octanoic and decanoic acids were 98 and 105%, respectively. Within-run CVs for octanoic acid at 0.5, 1.0, 2.5, 5.0, 7.5, and 10.0 micrograms/0.1 mL were 8.8, 7.9, 8.5, 6.5, 4.3, and 5.7%, respectively. For decanoic acid at identical concentrations, the CVs were 10.0, 7.4, 4.9, 4.0, 2.6, and 3.5%, respectively. For 10 children on MCT diet (45.9% of calories supplied as MCT) the mean concentrations of octanoic and decanoic acids were 44.2 and 27.0 mg/L, respectively. Presence of relatively "high" quantities of these acids in plasma may contribute to seizure control when MCT diet is prescribed for intractable childhood epilepsy.

Monitoring free valproic acid in epilepsy patients medicated with coanticonvulsants.

Methodology for monitoring free valproic acid (VPA) and experimental proof of intrapatient in vivo diurnally and disproportionately variable free VPA fractions has recently been reported. An inherent assumption in accepting therapeutic VPA plasma levels to be 50-100 micrograms/ml is that free fractions remain constant. This assumption is no longer tenable. Therefore, monitoring only VPA plasma levels could be misleading. The serial 9-h time-course (7 a.m. 0 10-1-4 p.m.) of free versus plasma VPA levels was investigated in 24 patients. Limits for diurnal fluctuations were (mean +/- SD): Group A (n = 14); 49.0 mg/kg; multiple equal dosing: Free VPA (micrograms/ml) 6.06 (1.55 to 12.62 (4.89), plasma VPA (micrograms/ml) 52.9 (11.6) to 84.2 (21.3), percent free VPA 11.5 (1.8) to 14.9 (2.5). Group B (n = 10); 30.6 mg/kg; b.i.d.: 12.0 (2.4) mg/kg a.m. and 18.7 (3.3) mg/kg p.m.: Free VPA 5.53 (1.04) to 9.92 (1.51), plasma VPA 52.0 (7.3) to 79.2 (9.6), percent free VPA 10.7 (1.6) to 12.5 (0.8). Reducing the dosage by 19 mg/kg (A to B) decreased VPA plasma levels by 6.9% nd free VPA levels by 28.9%. For B: y = 8.15 + 4.03 x; n = 10, r = 0.954, Sy.x = 1.38, when x = steady-state (7 a.m.) free VPA concentration and y = VPA mg/kg/day. The findings suggest that multiple dosing is unnecessary. Similar plasma levels with far less diurnal fluctuations of free levels are achievable by a smaller drug dose with approximately two-thirds of total daily dose being administered in the evening and one-third in the morning.