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Am J Physiol Heart Circ Physiol 282: H704-H716, 2002; doi:10.1152/ajpheart.00580.2001
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Vol. 282, Issue 2, H704-H716, February 2002

Carbamazepine increases atherogenic lipoproteins: mechanism of action in male adults

Susanne Brämswig, Anja Kerksiek, Thomas Sudhop, Claus Luers, Klaus Von Bergmann, and Heiner K. Berthold

Department of Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Treatment with carbamazepine (CBZ) affects cholesterol concentrations, but little is known about the precise nature and underlying mechanisms of changes in lipoprotein metabolism. We investigated prospectively the effects of CBZ on lipid metabolism in normolipemic adults. In 21 healthy males, lipoprotein and noncholesterol sterol concentrations were measured before and during treatment with CBZ for 70 ± 18 days. Thirteen subjects underwent kinetic studies of apolipoprotein-B (ApoB) metabolism with the use of endogenous stable isotope labeling. Lipoprotein kinetic parameters were calculated by multicompartmental modeling. Significant increases in total cholesterol, in ApoB-containing lipoproteins [very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL)], and in triglycerides, but not in high-density lipoprotein (HDL), were observed. Lipoprotein particle composition remained unchanged. Mean fractional catabolic and production rates of ApoB-containing lipoproteins were not significantly different, although mean production rates of VLDL and IDL were substantially increased (+46 ± 139% and +30 ± 97%, respectively), whereas mean production of LDL remained unchanged (+2.1 ± 45.6%). Cholestanol in serum increased significantly but not the concentrations of plant sterols (campesterol, sitosterol) and the cholesterol precursors (lathosterol, mevalonic acid). There was a significant correlation between the decrease in free thyroxine and the increase in IDL cholesterol. Treatment with CBZ increases mainly ApoB-containing lipoproteins. CBZ seems not to influence endogenous cholesterol synthesis or intestinal absorption directly. The increase is neither related to increased ApoB production nor to decreased catabolism but is rather due to changes in the conversion cascade of IDL particles, most likely as an indirect effect through a decrease in thyroid hormones.

cholesterol; stable isotopes; apolipoproteins


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

CARBAMAZEPINE (CBZ) is widely used as an anticonvulsant drug in adults and children. The drug is known to cause multiple metabolic alterations, among them changes in serum lipoprotein concentrations (3, 6, 8, 14, 16, 19-21, 29, 30, 32, 36, 42, 43, 46, 47, 51, 53, 54). The precise frequency and nature of these changes are unclear as are the underlying mechanisms of action. In many studies increased total and/or low-density lipoprotein cholesterol (LDL-C) concentrations were found (3, 6, 14, 16, 20, 21, 42, 43, 46, 47, 51), and elevated high-density lipoprotein cholesterol (HDL-C) is also frequently reported (3, 8, 19-21, 29, 36, 42, 47, 51, 53). The interpretation of most studies is limited due to unsatisfactory study designs; there are only four prospective studies (6, 16, 19, 21), whereas all other studies were cross-sectional and a variety of different control groups were used for comparison. In many studies there were antiepileptic comedications. Studies in children are difficult to interpret because lipoprotein profiles change with increasing age. In addition, it cannot be completely ruled out that epilepsy itself can lead to changes in lipoprotein profiles.

Cholesterol concentrations and especially the ratio of LDL-C to HDL-C are relevant determinants for the incidence and mortality from coronary heart disease (2, 9). There is some evidence that coronary heart disease is less common in patients with epilepsy (15, 27, 34), although these data are still uncertain. CBZ is known to be a powerful inducing agent of cytochrome P-450 enzymes (22, 24, 41), and its effects on lipoproteins have been largely attributed to its enzyme-inducing action (12, 31). Overall, however, there is very little information about the metabolic changes that are responsible for the effects of CBZ on lipids and no study controlled for confounding factors such as diet.

The aim of this trial was therefore to investigate prospectively in normolipemic healthy adult volunteers the effects of CBZ on lipoproteins and to employ intraindividual paired data statistics. Furthermore, we were interested in comprehensive analyses of lipid profiles including apolipoproteins. To gain insight into the mechanisms underlying changes in lipids, we conducted elaborate lipoprotein turnover studies using endogenous stable isotope-labeling tracer kinetics and multicompartmental modeling. In addition, we determined cholesterol precursors as markers of cholesterol synthesis (mevalonic acid, lathosterol) and plant sterols as markers of intestinal cholesterol absorption (noncholesterol sterols).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

Twenty-one healthy young male volunteers (age 21-34 yr) with normal lipid profiles were selected for this study. Lipoprotein concentrations were determined at baseline as three independent fasting blood samples on three different days within 1 wk. All participants were in good health (checked by medical history, physical examination, and safety laboratory, including thyroid function tests and a resting electrocardiogram). None of the subjects were taking drugs. Their anthropometric characteristics are given in Table 1, and their baseline lipoprotein profiles are given in Table 2. All subjects provided written informed consent. The study protocol was approved by the Ethics Committee of the Medical Faculty of the University of Bonn, and all procedures were performed in accordance with the current revision of the Helsinki Declaration.

                              
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  		Table 1.   Characteristics of 21 male volunteers at baseline


                              
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  		Table 2.   Lipoprotein profiles of 21 male volunteers at baseline and percent changes from baseline during treatment with carbamazepine

After inclusion, each participant started with treatment of the antiepileptic drug carbamazepine (Tegretol, Ciba-Geigy; Wehr, Germany). To minimize side effects, the dosage was gradually increased during the first 10 days of medication, reaching a constant dosage regimen of 400 mg CBZ bid from day 11 on. During medication, compliance, drug tolerability, and adverse events were checked and recorded. On day 10 and thereafter, CBZ concentrations were determined at weekly intervals. Lipoprotein profiles were determined at regular intervals during treatment to evaluate the time course of lipoprotein changes.

Protocol

Thirteen subjects underwent kinetic studies of lipoprotein metabolism using stable, nonradioactive isotopes. Each of these participants was studied twice, once during treatment with CBZ and once after cessation of the drug for at least 8 wk.

The turnover study protocol began in the morning after an at least a 12-h fast. Subjects were admitted to the metabolic ward at 7:00 AM. They were studied in the fasted state and remained supine during the time of infusion and 4 h after its termination. One hour before the infusion was started, each participant drank 400 ml of mineral water to standardize their hydration state. Noncaloric and caffeine-free beverages were allowed ad libitum from 3 h after start of the infusion and thereafter.

One intravenous line was inserted into the left arm for infusion with the deuterated amino acid L-[5,5,5-2H3]leucine ([D3]leucine; MassTrace, Woburn, MA) dissolved in buffered saline. The infusion had been shown to be pyrogen free and sterile. A second line was placed intravenously for blood sampling in the opposite arm. At time 0, tracer administration was started with a bolus injection of [D3]leucine of 1.4 mg/kg body wt immediately followed by a continuous (constant) infusion of [D3]leucine (1.4 mg · kg-1 · h-1) for a period of 10 h. Four hours after the infusion was stopped, subjects received dinner and then fasted again until after the 24-h blood sample had been drawn.

Blood samples were drawn during the infusion and on the following days in EDTA tubes to which had been added a mixture of inhibitors of enzymes and bacterial growth (sodium azide, chloramphenicol, gentamicin sulfate, and aprotinin). Blood samples were collected at baseline and at various intervals during the infusion and for another 19 days (days 1, 2, 3, 4, 5, 7, 10, 14, and 19) after the end of infusion to determine isotopic enrichment of leucine in plasma as well as in apolipoprotein B (ApoB) in different lipoprotein fractions. During the turnover study, plasma aliquots were taken at seven different time points (four of these were during the infusion) for determination of the ApoB pool size. A 12-h urine collection was conducted during each infusion day.

Dietary protocol and body composition. Dietary intake and body composition were determined thoroughly in the subjects undergoing turnover studies. No specific dietary advice was imposed before the studies. Instead, each participant had to fill in a 7-day food record documenting nutritional intake during the week before onset of the first turnover study (CBZ period). These food records were then handed out to the subjects, and they were instructed to follow this first food record during the week before the second turnover study (control period) started. They were asked in addition to keep a second 7-day food record during that time to assess possible effects of variation in nutritional intake.

Body weights and body composition (including body fat and body lean mass, intra- and extracellular water) were determined by bioelectrical impedance analysis (Multi Frequency Analyzer B.I.A. 2000-M; Data Input; Frankfurt, Germany) in combination with the manufacturer's software Nutri4.

Analytic Methods

Carbamazepine determination. CBZ serum levels were measured by a fluorescence polarization immunoassay with an automatic analyzer (TDx, Abbott; Wiesbaden, Germany).

Lipoprotein chemistry. Cholesterol and triglycerides were measured enzymatically in total plasma as well as in the lipoprotein fractions very-low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and LDL according to the cholesterol oxidase phenol 4-aminophenazone and the glycerol phosphate oxygen phenol 4-aminophenazone method (Boehringer Mannheim), respectively. HDL-C was determined enzymatically after precipitation of ApoB-containing lipoproteins (7). The concentration of LDL-C was also calculated according to the Friedewald formula (17). The coefficient of variation for cholesterol measurements was 0.99% for total cholesterol, 2.64% for LDL-C, 2.22% for HDL-C, and 1.14% for triglycerides (laboratory day-to-day variation).

ApoB concentration in plasma and lipoprotein fractions was determined with a noncompetitive, enzyme-linked immunoabsorbent assay using immunopurified polyclonal antibodies on the Beckmann Array-360 System (Beckmann Instruments; Munich, Germany).

Lipoprotein separation. Isolation of the lipoprotein fractions VLDL, IDL, and LDL was performed using preparative sequential density ultracentrifugation. At first, a (3.2 ml) polycarbonate tube was filled with a 1.5-ml aliquot of plasma and a 1.5 ml sodium chloride density solution (0.9%) and centrifuged at 16°C in a TLA 100.4 rotor for 2.5 h at 100,000 g in an Optima TLX centrifuge (Beckmann Instruments). All density solutions used contained 1 g/l EDTA. After centrifugation, the supernatant containing VLDL (density < 1.006) was removed after tube slicing with a CentriTube Slicer (Beckmann Instruments). To isolate the IDL fraction (density = 1.006 to density = 1.019), the remaining infranatant was transferred into a new tube adding a second, more dense sodium chloride density solution (4.5%) and an analogous centrifugation step was started. After tube slicing and transfer of the infranatant in a third new tube was completed, the centrifugation procedure was repeated, this time using an even more dense sodium chloride density solution (15%) to separate the LDL lipoprotein fraction (density = 1.019 to density = 1.063). All isolated lipoprotein fractions were aliquoted and stored frozen for measurement of cholesterol, triglyceride, and ApoB concentrations as well as for ApoB separation for leucine enrichment determination.

Isolation of plasma amino acids. Plasma free amino acids were isolated from 0.5 ml of plasma by cation exchange chromatography. Disposable columns were prepared with 0.6 ml of AG-50W-X8 resin (Bio-Rad Laboratories; Hercules, CA) that had been stored in sodium hydroxide. The amino acids were eluted with ammonium hydroxide, and thereafter the samples were dried with the use of a Savant SpeedVac (Savant Instruments; Framingdale, NY).

Amino acid derivatization. For derivatization the amino acids were esterified with N-propanol and then derivatized with N-heptafluorobutyric anhydride (Pierce; Rockford, IL) to form stable volatile molecules for gas chromatography separation (4). The samples were dissolved in ethyl acetate and transferred into vials for gas chromatography-mass spectrometry analysis.

ApoB separation. The ApoB of the lipoprotein fractions VLDL, IDL, and LDL was isolated and purified using a previously described isopropanol precipitation method (13). The precipitated protein was quantitatively hydrolyzed to amino acids with constant boiling HCl for 24 h at 110°C. The HCl was subsequently evaporated in the SpeedVac centrifuge. The amino acids obtained were then also subjected to cation exchange chromatography and subsequently derivatized.

Determination of enrichment and calculation of tracer-to-tracee ratio. Isotopic enrichment determination of leucine was performed on a Fisons GC8060/Trio 1000 quadrupole system (ThermoQuest; Egelsbach, Germany). The samples were injected into a 30-m × 0.32-mm, 0.25-µm DB-5MS capillary column (J&W Scientific; Rancho Cordova, CA). Mass spectrometry was performed by negative ion chemical ionization with methane as the reagent gas. Selected ion monitoring of the leucine peak was performed for 2H3 enrichment using the [M - HF] and [M - HF + 3] isotopomers (mass-to-charge ratio = 349 and 352), respectively, where M is mass and HF is hydrogen fluoride. Measurements were done in quadruplicates at baseline and in triplicates in subsequent samples. Because of the nonnegligible mass associated with stable isotope tracers, it was necessary to transform enrichment data to tracer-to-tracee ratios (10).

Kinetic analysis. A multicompartmental model (Fig. 1) was used to describe VLDL-, IDL-, and LDL-ApoB isotopic enrichment data. Each compartment or pool represents a group of kinetically homogenous particles. In the present study, the SAAM II program (SAAM Institute; Seattle, WA) was used to fit the observed tracer data to the model. Metabolic parameters were subsequently derived from the model parameters giving the best fit. The model consists of a precursor compartment of amino acids (compartment 1) and the delay compartment (compartment 2), which accounts for the time required for synthesis and secretion of VLDL ApoB into plasma. Plasma leucine tracer-to-tracee data were fit using the forcing function to drive the appearance of tracer (amino acid) in the compartment model. The purpose of the forcing function is to decouple components of the system under investigation, which obviates the need to model leucine metabolism separately and takes into account the recycling of tracer and thus minimizes its effect on the slow-turnover compartments. Mathematically, the forcing function replaces the amount of tracer in compartment 1 with the value of the amino acid enrichment data used as forcing function (FF) at the same time. In other words, the value of q1(t), the amount of material and tracer in compartment 1 at time t, is replaced by the term q1 × FF(t). We used plasma data to decouple the kinetics of free amino acid from that of the tracer in ApoB.


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  		Fig. 1.   Multicompartmental model for apolipoprotein B (ApoB)-100 metabolism. Isotopic enrichment data were fit to tracer-to-tracee ratios. Compartment 1 shows the precursor with plasma leucine enrichment data used as forcing function. Compartment 2 is the delay compartment for intracellular hepatic synthesis and secretion of very-low-density lipoprotein (VLDL)-ApoB-100. Compartments 11, 12, and 13 represent one rapid and two slow VLDL turnover compartments, respectively. Compartments 21 and 22 correspond to a rapid and slow intermediate density lipoprotein (IDL) turnover compartment, and compartment 31 shows the low-density liporprotein (LDL) compartment. Numbers on arrows given as means ± SD are fractional rate constants (k values) expressed in pools per hour for the control (top) and carbamazepine (CBZ) period (bottom).

The model assumes that all ApoB enters plasma through compartment 11. Compartments 11 and 12 are used to describe the kinetics of ApoB in the VLDL subfraction. They represent a delipidation cascade (minimal), as originally described by Phair et al. (40), and represent a rapidly and slowly turning over pool. In some subjects a third, slow-turnover compartment was required to model the data (compartment 13). It was assumed that the fraction of each compartment in the cascade converted to this slow-turnover VLDL compartment is the same. The VLDL particles in compartment 12 can be converted to IDL or can be removed directly from plasma. The IDL section of the model includes compartments 21 and 22, rapid- and slow-turnover pool of IDL particles, respectively. Compartment 22 was not required in some of the subjects. Particles in compartment 21 can be converted to the slow IDL compartment, to LDL, or can be removed directly from plasma. In our model, LDL-ApoB kinetics were described by one compartment only (compartment 31). LDL-ApoB can be derived from IDL (compartment 21) or directly from VLDL (compartment 11).

After we fit the tracer-to-tracee data to the model, ApoB fractional catabolic rates (FCR) and production rates (PR) were determined using the best fit. The FCR for all lipoprotein fractions was calculated by adding the individual rate constants, termed k values, leaving the compartments. For VLDL and IDL turnover, we used a weighted, related to mass distribution, average of the turnover rates of individual pools.

We were able to apply this model to all subjects studied under CBZ medication and under control conditions; however, not all compartments were needed in all subjects. In particular, the slowly turning over VLDL pool (compartment 13) was not necessary to describe the kinetics in three subjects, and the slowly turning over IDL pool (compartment 22) was not necessary in three other subjects. On the other hand, direct conversion (shunt pathway) of VLDL (compartment 11) to both IDL and LDL was necessary to describe the data of all participants, which is in contrast to many studies in the literature. Moreover, a direct catabolism pathway leaving compartment 11 could not be identified. In any event, within one volunteer we always used the identical compartmental model. If transfer coefficients appeared not to be necessary in individual subjects, indicated by coefficients <0.001, the k values were deliberately set to zero to obtain more reliable parameter estimation for the remaining adjustable parameters. All parameters were fitted as adjustables.

Determination of plant sterols, cholestanol, and lathosterol. The plant sterols campesterol (24-methyl-cholesterol) and sitosterol (24-ethyl-cholesterol), the 5alpha -cholesterol derivative cholestanol, and the endogenous cholesterol precursor lathosterol were determined by gas liquid chromatography as previously described (5). The concentrations of these compounds are expressed as ratios to cholesterol (µg per mg) to correct for changes in cholesterol concentrations.

Determination of mevalonic acid. Mevalonic acid was determined in serum and in urine as previously described in detail using a highly sensitive isotope dilution gas chromatography-mass spectrometry method (25).

Determination of 6-beta -hydroxycortisol. 6-beta -Hydroxycortisol, a reliable indicator of the degree of enzyme induction, was measured in urine using a sandwich-ELISA (Stabiligen; Nancy, France).

Statistical Analysis

The results are presented as means ± SD, unless stated otherwise. Wilcoxon signed rank sum tests were used to compare the results obtained during CBZ and placebo therapy. Multiple regression analysis was employed to determine which kinetic parameter had significant effects on the primary outcome measure, change in LDL cholesterol concentrations. All statistical analyses were calculated using StatView Version 5 (SAS Institute; Cary, NC).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Dosage, Compliance, and Tolerability

Standard drug doses were 400 mg bid. They had to be increased to 400 mg tid in eight subjects (subjects 3, 4, 7, 10, 11, 12, 18, and 21) because plasma concentrations remained low due to the autoenzyme-inducing effects of CBZ. These subjects received a dose increase after 55 ± 14 (means ± SD) days to maintain the desired CBZ plasma concentration. The means ± SD CBZ concentrations achieved after 2, 4, 6, 8, 10, and 12 wk were 7.9 ± 0.3, 6.7 ± 0.4, 6.9 ± 0.4, 6.2 ± 0.4, 6.4 ± 0.6, 6.3 ± 0.5 µg/ml, respectively. Drug compliance was good, and the mean concentration for all participants was 6.5 ± 0.6 mg/dl. The mean duration of treatment for all subjects was 70 ± 18 days (minimum: 38, maximum: 103 days). The treatment was generally tolerated well. Safety parameters, including blood cell count, serum electrolytes, liver function tests, creatinine, and thyroid parameters, remained within their respective normal range. Thyroid function parameters, however, were significantly changed despite remaining in the normal range. Free thyroxine concentrations decreased by 18 ± 12% (from 1.44 ± 0.18 to 1.20 ± 0.10 ng/dl, P = 0.0017), free triiodothyronine decreased slightly but not significantly by 9 ± 16% (from 3.7 ± 0.55 to 3.3 ± 0.6 ng/l, P = 0.10), and thyroid-stimulating hormone increased by 33 ± 29% (from 1.54 ± 0.87 to 2.50 ± 1.87 mU/l, P = 0.06). Changes in these parameters did not correlate with changes in total cholesterol or LDL-C. There was a significant increase of 138 ± 115% in gamma -glutamyltransferase (gamma -GT, from 11 ± 4 to 26 ± 19 U/l, P < 0.001). Other liver function tests were not changed. Creatinine clearance as determined from 12-h urine collections in the subjects undergoing infusion studies remained unchanged (data not shown).

Body Weight, Body Composition, and Dietary Records

As presented in Table 1, all subjects were of normal body weight (body mass index = 23.4 ± 1.7 kg/m2). There was a significant increase in body weight (+1.9 ± 1.2%; P < 0.002) during treatment with CBZ, which was accompanied by significant increases in lean body mass (+2.0 ± 2.3%, P = 0.007), and in intra- and extracellular water by the same order of magnitude (+1.5 ± 1.8, P = 0.007 and +2.7 ± 3.6%, P = 0.023, respectively). Body fat mass remained unchanged. The diet of the subjects was in line with an average central European isocaloric diet, containing a relatively high percentage of calories from fat (36 ± 4%) and saturated fatty acids (14 ± 2%). According to the reported alcohol consumption quantities, the subjects had largely followed the advice to restrain from alcohol during the periods of CBZ treatment and during the week before control infusions. Most importantly, calories and the relative contribution of macronutrient of dietary intake were virtually unchanged during the respective weeks before the two turnover studies, with the exception of a slight but significant increase in monounsaturated fatty acids by 11 ± 13% (Table 3).

                              
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  		Table 3.   Seven-day food records before turnover protocols

Lipoprotein Concentrations and Composition

The distribution of the ApoE phenotype was similar as it is in the general population. Nineteen of twenty- one subjects had at least one ApoE3 allele; only subject 16 had phenotype E4/E4 and subject 21 had phenotype E2/E4. Table 2 summarizes the lipoprotein profiles at baseline and the respective percent changes during CBZ treatment. All subjects were normolipemic at baseline. Mean total cholesterol concentrations at baseline were 190 ± 29 mg/dl, mean LDL-C concentrations were 126 ± 26 mg/dl, and mean HDL-C was 45 ± 8 mg/dl. Triglyceride concentrations (mean 94 ± 38 mg/dl) were generally <150 mg/dl, with the exception of one subject.

During CBZ treatment there were significant increases in all lipoprotein fractions except for HDL-C. Total cholesterol increased by 13 ± 15% (P = 0.002), LDL-C increased by 17 ± 21% (P = 0.004), and triglycerides increased by 18 ± 31% (P = 0.028). The mean values of HDL-C were virtually unchanged (+4 ± 16%, P = 0.45). There was no relationship between changes in LDL-C and CBZ plasma concentrations.

Table 4 shows the lipoprotein concentrations in the 13 volunteers that were studied in more detail with turnover procedures. There was a substantial and significant increase in both cholesterol and ApoB concentration in all ApoB-containing lipoprotein fractions. This increase was most pronounced in IDL (cholesterol, +38 ± 35%; ApoB, +33 ± 36%), followed by VLDL (cholesterol, + 29 ± 21%; ApoB, +29 ± 23%) and LDL (cholesterol, + 10 ± 14%; ApoB, +13 ± 14%). There was also a significant increase in total serum triglycerides (+21 ± 27%). Triglycerides in lipoprotein subfractions increased by 27 ± 37% in VLDL (P = 0.03), 60 ± 80% in IDL (P = 0.035), and 35 ± 41% in LDL (P = 0.011), individual data not shown.

                              
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  		Table 4.   Cholesterol and ApoB concentrations in individual lipoprotein fractions as determined by sequential density ultracentrifugation and total triglyceride concentrations

Table 5 shows the average changes in lipoprotein particle composition, as indicated by ratios of cholesterol to ApoB, cholesterol to triglycerides, and triglycerides to ApoB. None of these ratios showed significant differences. The relation of cholesterol to ApoB and to triglycerides remained remarkably stable, indicating that CBZ-induced changes altered the content of these lipoprotein particles in a similar unidirectional fashion. Triglyceride content in relation to ApoB seems to increase in denser lipoproteins (IDL, LDL), although this tendency also did not reach statistical significance.

                              
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  		Table 5.   Changes in the ratios of lipid components indicate changes in lipoprotein particle composition

Lipoprotein Kinetics

We used isotopic enrichment data of VLDL and IDL ApoB up to 120 h and LDL ApoB up to 168 h to fit the data to the multicompartment model. The model used and the kinetic parameters derived (top, control and bottom, CBZ) are shown on Fig. 1. Original data and the best fit of one subject are shown as an example on Fig. 2, and the data of all subjects are shown in Table 6. The mean fractional catabolic rates and mean production rates of all lipoprotein classes did not show significant differences between the control and CBZ phase. There were major interindividual differences in the response of these metabolic parameters to CBZ treatment. Although there were no statistically significant differences, it is noteworthy that production rates of VLDL and IDL lead to substantial average increases, whereas production of LDL and the FCRs of all three lipoprotein classes remained unchanged. Linear regression analyses showed that the percent changes in FCRs and production rates were highly correlated (VLDL, r = 0.99, P < 0.0001; IDL, r = 0.96, P < 0.0001; LDL, 0.94, P < 0.0001). Baseline ApoB concentrations in LDL had no influence on the change in FCRs and PRs of all lipoprotein classes, and also the percent changes in LDL ApoB were not related to the FCR and PR values. Multiple regression analysis using the percent change in LDL ApoB as the dependent parameter showed independence from changes in FCRs and production rates.


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  		Fig. 2.   VLDL-, IDL- and LDL-ApoB tracer-to-tracee ratios of observed data (symbols) and calculated fits (lines) using the multicompartmental model in a representative normolipemic healthy volunteer.


                              
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  		Table 6.   FCR and PR of VLDL ApoB, IDL ApoB, and LDL ApoB as estimated by multicompartmental modeling

Plant Sterols, Cholestanol, and Cholesterol Synthesis Precursors

There was a significant increase by ~12% in cholestanol (Table 7). The increase in sitosterol was in the same order of magnitude and reached borderline significance. Campesterol and lathosterol were unchanged as were mevalonic acid concentrations in serum and in urine.

                              
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  		Table 7.   Serum concentrations of plant sterols, cholestanol, and the endogenous cholesterol synthesis precursor lathosterol

6-beta -Hydroxycortisol Concentrations

During treatment with CBZ a significant mean increase of 300% (range: 76-660%) in concentration of 6-beta -hydroxycortisol was observed. The individual changes in 6-beta -hydroxycortisol did not correlate with changes in LDL-C.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

As the main result of this prospective study in normolipemic volunteers, we found unexpectedly no change in HDL-C concentrations during treatment with CBZ. A marked increase in HDL-cholesterol was seen only in two subjects (subjects 2 and 20). This is in contrast to most other studies that have reported a significant increase in HDL-C concentration (3, 8, 20, 30, 36, 42, 47). The present results are well in accordance with those from a prospective study of Isojärvi et al. (21), who found a significant increase in HDL-C in patients with idiopathic epilepsy for the total group investigated but could not be confirmed for the subgroup of men.

In addition, in the present study, a significant increase was observed in triglycerides and in total and LDL-C concentrations by 18%, 13%, and 17%, respectively. Other studies have also shown markedly elevated LDL-C levels (8, 14, 21, 42, 43, 46, 47, 51), although not always being consistent for both males and females (8, 20, 21, 42, 47). Hindi et al. (20) found a significant increase in LDL-C in females, whereas Calandre et al. (8) only observed an increase in men. Isojärvi et al. (21) and Sudhop et al. (47) found significantly higher LDL-C concentrations in both sexes compared with a control group.

Elevated total cholesterol, LDL-C, and triglyceride levels are known cardiovascular risk factors, whereas a protective role has been established for HDL-C (2). The ratios of total cholesterol to HDL-C and LDL-C to HDL-C, known as relevant predictors for the prognosis of coronary heart disease, changed to more unfavorable ratios in this study with borderline significant differences (4.4 ± 1.0 vs. 4.7 ± 0.9, P = 0.073, and 2.9 ± 0.8 vs. 3.2 ± 0.8, P = 0.067, respectively). Similar results were observed in most studies comparable in design to our study (20, 42, 47, 54). There is some evidence that coronary heart disease may be less common in patients with epilepsy (15, 27, 34), raising the question whether drugs like CBZ contribute to a more favorable lipid profile and may thus be responsible for this observation. From the changes in lipid profiles in this and the aforementioned studies, especially with regard to elevated LDL-C and triglycerides in men (with unchanged HDL-C levels), a protective effect of long-term CBZ treatment to the risk for cardiovascular disease has to be questioned.

Apart from drug treatment effects, it cannot be excluded that the disease itself may affect lipoprotein concentrations, although there is no publication having explicitly addressed this issue. Therefore, to rule out a possible influence on changes in lipoprotein metabolism caused by epilepsy, healthy individuals were investigated in the present study. In contrast to this, previously published trials examining the effects of anticonvulsant drugs on lipoprotein metabolism were mostly conducted in patient cohorts (mainly in epileptic patients).

Shortcomings of most studies investigating patients receiving various drugs or combinations of anticonvulsant drugs are small sample sizes if subgroup analyses are made for patients receiving only monotherapies. In some studies, especially in the CBZ-treated subgroups, the number of males was small (6, 8, 30, 53). To exclude the influence of other drugs and to take sex differences in lipoprotein metabolism into account, only male subjects receiving monotherapy with CBZ were investigated in the present study.

Contradictory results in lipoprotein concentrations during treatment with anticonvulsant drugs may at least in part be due to differences in the quality of lipid/lipoprotein determinations. Usually little is known about the quality of lipid determinations. Most studies are based on one single measurement of the lipoprotein concentration that does not take into account intraindividual variations. A single measurement of lipid concentrations may cause misleading interpretations of the relationship between lipoprotein concentration and the parameter(s) of interest. To ensure high-quality measurement in the present study, lipoprotein concentrations were determined as the means of three independent blood samples. In 23% of all subjects interday variation coefficients of greater than 10% were found for LDL-C as were 14% and 18% for total cholesterol and HDL-C, respectively. We therefore conclude that on the basis of precise measurements of lipoprotein concentrations, reliable estimation of changes in concentrations was possible. In addition, during the turnover studies, lipid concentrations (cholesterol, ApoB, and triglycerides) in the lipoprotein subfractions VLDL, IDL, and LDL were determined as means of seven independent blood samples in the control and CBZ period.

Furthermore, 7-day food records were assessed to control for dietary intake during the week before the infusion day in both periods. Nutritional intake may be an important influencing and/or confounding factor on lipoprotein metabolism. In this study, caloric and macronutrient intakes were virtually unchanged. An influence of monounsaturated fat on hepatic ApoB production could not be observed; the slight shift to a more favorable intake of monounsaturated fat did not correlate with changes in VLDL-ApoB FCR and VLDL-ApoB PR. We conclude that reliable results of kinetic parameters in ApoB metabolism were assessed in both the control and CBZ treatment period.

The changes in lipoprotein concentrations observed during the intake of CBZ may possibly be due to the direct influence of CBZ on physiological mechanisms during endogenous synthesis or catabolism of cholesterol. An influence of CBZ on endogenous cholesterol synthesis in the liver has been discussed before (6, 28). The concentration of mevalonic acid in plasma reflects the activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and was determined as an indicator of cholesterol synthesis in vivo in our study. Because concentrations of mevalonic acid in plasma might be subject to diurnal rhythm (38), mevalonic acid in urine and lathosterol concentrations in serum were determined as well. The latter is considered to be a valid indicator of whole body cholesterol synthesis in humans (23). Both changes in mevalonic acid and lathosterol concentrations (expressed as ratio lathosterol to cholesterol) did not correlate with changes in VLDL-ApoB FCR and PR (even after correcting for body weight), although during treatment with CBZ, mevalonic acid in serum was positively correlated with VLDL-ApoB and VLDL-C concentration (r = 0.87, P = 0.01; r = 0.64, P = 0.035, respectively). A direct relation between the hepatic VLDL-ApoB secretion and cholesterol precursor had been demonstrated in some (44, 52), but not in all, studies (45). Sudhop et al. (47) have also shown that the concentration of lathosterol is unchanged in CBZ-treated epileptic patients during long-term medication. From these results we conclude that CBZ does not directly influence endogenous cholesterol synthesis. It seems therefore unlikely that the increase in LDL-C concentration in this study is due to an increase in HMG-CoA reductase activity. There are, however, other microsomal enzymes involved in lipid metabolism as possible targets of direct CBZ effects. Recently, overexpression of the microsomal triglyceride transfer protein has been shown to increase VLDL-ApoB and VLDL-triglyceride secretion in the liver (49). Whether treatment with CBZ might affect these microsomal processes can only be speculated about.

Serum levels of plant sterols are regulated by their dietary intake, intestinal absorption, and biliary secretion. They have been reported to correlate negatively with cholesterol synthesis and positively with cholesterol absorption (33). In this study, sitosterol and campesterol concentrations showed a tendency toward increase during drug treatment, although not reaching statistical significance. Baseline lathosterol correlated negatively (r = -0.45, P = 0.045) with campesterol levels, but not with sitosterol. During treatment with CBZ, the concentration of sitosterol and campesterol showed no correlation with mevalonic acid concentration and its change as did percent change of lathosterol. We conclude from these results that an influence of treatment with CBZ on cholesterol absorption is unlikely.

The plasma concentrations of CBZ may have an influence on the extent of changes in lipoproteins, since low drug levels may be devoid of metabolic and therapeutic effects. In this study, mean CBZ concentrations were found to be in the lower therapeutic range. They did neither correlate with total cholesterol, LDL-C, or HDL-C or triglycerides nor with the percent lipoprotein changes during drug administration. Other authors (6, 8, 46, 47, 51) have also reported no correlation between CBZ and lipoprotein concentrations, although sometimes higher CBZ levels in serum (7-9 µg/dl) were achieved. The ratios of daily CBZ doses per kilogram body weight to the plasma concentrations achieved are shown in Fig. 3. This level-to-dose ratio could be of greater value to correct for autoinducing effects of the drug, because drug dose has been shown to be a better predictor of metabolizing capacity than plasma levels (39). There was a significant linear relationship between dosage corrected for body weight and plasma concentrations. Changes in LDL-C levels were however not correlated with level-to-dose ratios (Fig. 4). These results are in accordance with other studies (6, 30, 47) and speak against the enzyme induction being the major mechanism underlying LDL-C increase. In the literature, the enzyme-inducing properties of CBZ have usually been used to explain changes in lipoprotein profiles. CBZ acts primarily as microsomal enzyme inducer of the cytochrome P-450 system in the liver and intestine (28, 39, 48). In contrast to CBZ, other drugs that have been studied for their enzyme-inducing effects on serum lipoprotein concentrations failed to affect lipid profiles in the same manner. For example, rifampicin and antipyrine do not alter lipoprotein concentrations (35), but ketoconazole, a cytochrome P-450 inhibitor, has been found to decrease lipoprotein (total and LDL-C) levels (18). Therefore, enzyme-inducing properties as a general principle of cholesterol increase are unlikely.


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  		Fig. 3.   Plasma concentration of CBZ (µg/ml) in relation to drug dose given corrected for body weight (mg · kg body wt-1 · day-1). A linear relationship could be observed (r = 0.42, P = 0.06); ignoring one data point as an outlier (possible compliance problem) would have resulted in a highly significant correlation (r = 0.64, P = 0.002). Level-to-dose ratios were in a very narrow range (0.54 ± 0.09). Individual CBZ concentrations of 21 subjects are means ± SD of two independent measurements during drug treatment at the end of the treatment phase.



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  		Fig. 4.   Percent change in LDL-cholesterol concentration during treatment with CBZ in relation to CBZ level-to-dose ratios (calculated as ratio of daily dose per kg body weight to the plasma concentration achieved). Percent change in LDL-cholesterol was calculated between baseline (as mean value of 3 independent fasting blood samples on 3 different days), and mean value of 3 independent measurements during treatment with CBZ at the end of treatment period.

A significant increase in gamma -GT concentrations during CBZ treatment support the role of CBZ as inducing agent. On average, gamma -GT concentrations increased by 138%. Isojärvi et al. (21) have also shown an increase in gamma -GT concentrations during CBZ treatment in patients with idiopathic epilepsy. But it still has to be considered that changes in liver enzyme concentrations may not sufficiently prove the enzyme-inducing effects because nonmicrosomal factors may influence gamma -GT concentrations (28). To further verify the microsomal effects of CBZ, the concentration of 6-beta -hydroxycholesterol in urine, a reliable indicator of enzyme induction, was found to be increased during treatment with CBZ. A correlation between changes in LDL-C and 6-beta -hydroxycholesterol, however, was not observed.

The enzyme-inducing effects of CBZ were thought to be responsible for changes in lipoprotein concentrations as well as for changes in thyroid and sex hormone concentrations during treatment with CBZ by some authors (11, 12, 32). It has been assumed that a strong induction of these cytochrome P-450 enzymes is associated with high levels of HDL-C (and low LDL-C) (8, 32). This could not be confirmed in the present study. Nevertheless, a decrease in concentrations of free thyroxine and free triiodothyronine demonstrated an enhanced plasma clearance during treatment with CBZ caused by induction of hormone-metabolizing enzymes. In other studies a decrease in ApoB-containing lipoprotein particles during thyroxine therapy was described (1, 26, 37, 50). Interestingly, in the present study changes in thyroxine and IDL-C concentrations during CBZ administration showed a marked negative correlation (r = -0.81, P = 0.015). These results are in accordance with a study by Asami et al. (1), who found that the IDL fraction correlates inversely with free thyroxine serum levels, suggesting that thyroxine promotes the conversion of IDL to LDL, possibly by its stimulatory effect on hepatic lipase activity. Because, from the results of our kinetic modeling study, the conversion of IDL into LDL was diminished during treatment with CBZ, we assume that reduced thyroxine concentrations may be responsible for diminished activity of the lipoprotein delipidation cascade as a consequence of decreased lipase activities. Increased triglyceride content of IDL particles are well in line with this possible mechanism. It still has to be proven in further studies whether CBZ directly shows an influence on lipase activities. The CBZ-induced changes in the kinetic parameters of lipoprotein turnover showed otherwise a large variability between subjects, and there was no association between changes in lipoprotein concentrations. Thus drug effects on lipoprotein secretion or catabolism can be excluded as the responsible mechanism. Because of the elaborate and costly character of the turnover procedures, we were not able to perform a true randomized crossover design to determine lipoprotein kinetics; however, we believe that this did not affect the results.

In conclusion, the present trial indicates that the increase in LDL is neither related to its increased production nor to decreased catabolism of ApoB-containing lipoproteins but rather to changes in conversion of IDL particles. Treatment with CBZ does not directly influence endogenous cholesterol synthesis. It seems unlikely that induction of cytochrome P-450 enzymes influences cholesterol metabolism directly. Whether the increase in LDL-C concentrations is mediated through effects of CBZ on thyroid hormones has to be clarified. The influence of long-term CBZ treatment with regard to elevated total and LDL-C concentrations on cardiovascular risk should be reevaluated in epileptic patients.


    ACKNOWLEDGEMENTS

We express our thanks to all volunteers for participation in this study. The authors thank Dr. G. Röhrig for excellent clinical assistance. We are indebted to H. Prange and K. Willmersdorf for excellent technical assistance. We thank Drs. S. Westphal and J. Dierkes for performing the ApoE analysis and to Dr. M. Zühlsdorf for determination of 6-beta -hydroxycortisol.


    FOOTNOTES

This study was supported by a research grant from Bundesministerium für Bildung und Forschung (01EC9402) and by funds from the Center for Cardiovascular Diseases Institute for Clinical Research at Rotenburg an der Fulda.

Address for reprint requests and other correspondence: H. K. Berthold, Institute for Clinical Research/Dept. Clinical Pharmacology, Center for Cardiovascular Diseases Rotenburg, 36199 Rotenburg a.d. Fulda, Germany (E-mail: berthold{at}uni-bonn.de).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

10.1152/ajpheart.00580.2001

Received 3 July 2001; accepted in final form 2 October 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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