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DRUG METABOLISM |
From Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo-SP, Brazil (P. M. Cerqueira); Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil (E. B. Coelho, T. J. M. Geleilete); and Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil (G. H. Goldman, V. L. Lanchote).
Address for reprints: Vera Lucia Lanchote, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n. Campus da USP, 14040-903, Ribeirão Preto, SP, Brazil; e-mail: lanchote{at}fcfrp.usp.br.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-hydroxymetoprolol (
) and (R)-metoprolol acidic metabolite (
), the latter resulting in the plasma accumulation of (S)-metoprolol (
). Patients with chronic renal failure presented plasma accumulation of the 4 -hydroxymetoprolol isomers and of both metoprolol acidic metabolite enantiomers. A 50% reduction in ClR does not explain the 3- to 4-fold plasma accumulation of metoprolol acidic metabolite in this group, suggesting that other pathways of metoprolol elimination are affected in chronic renal failure in addition to renal excretion. Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite.
Key Words: Metoprolol • stereoselectivity • metabolism • pharmacokinetics • chronic renal failure
Metoprolol, a selective ß1-adrenergic receptor antagonist, is used in clinical practice in the racemic form for the treatment of myocardial infarction, cardiac failure, and arterial hypertension. The (S)-metoprolol enantiomer has about 500-fold more affinity for the ß1-adrenergic receptor than its (R)-antipode.3,4
Most of the data concerning enantioselectivity in metoprolol pharmacokinetics have been obtained in studies in which a single dose was administered to healthy volunteers.5-7 Only 1 multiple-dose study was reported in hypertensive patients, showing the occurrence of enantioselectivity in the pharmacokinetics of metoprolol with plasma accumulation of the (S)-eutomer and increased renal excretion of its (R)-enantiomer.8
Metoprolol is not a substrate for P-glycoprotein.9 Renal excretion of unchanged metoprolol is less than 10%, indicating that metabolism is the main process responsible for its elimination.10 The metabolites of metoprolol (Figure 1) are generated by aliphatic hydroxylation (-hydroxymetoprolol [OHM], 
10%), oxidative deamination (N-dealkylmetoprolol, <10%), and O-demethylation (O-demetylmetoprolol, ODMM), with subsequent oxidation (metoprolol acidic metabolite [MAM], 65%).11 Metoprolol metabolism involves different cytochrome P450 (CYP) enzymes, with CYP2D6 being responsible for approximately 70% of the biotransformation of metoprolol in vivo.5,12 In human liver microsomes, -hydroxylation is catalyzed by the polymorphic CYP2D6, and ODMM formation is partially dependent on this enzyme.13,14
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In human liver microsomes, ODMM is preferentially formed by (R)-metoprolol oxidation, whereas (S)-metoprolol is mainly -hydroxylated.14,15 Hydroxylation of the aliphatic chain of metoprolol adds a new chiral center to the corresponding OHM, generating 4 optical isomers. In a clinical study with a single oral dose of rac-metoprolol administered to healthy volunteers (CYP2D6 extensive metabolizers), Murthy et al16 observed, by recovery of metoprolol and its metabolites from urine, the preferential formation of the new chiral center 1'R in relation to 1'S-OHM (1'R/1'S 3). The authors also observed enantioselectivity in the formation of ODMM, favoring the (R)-enantiomer, which confirmed the results obtained with human liver microsomes.16
CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics.17 In addition to the oxidative phenotype, enantioselectivity in the pharmacokinetics of metoprolol administered orally to extensive metabolizers (EM) is highly relevant in terms of the wide interindividual variability observed in the kinetic disposition of this drug.6,8,18,19 It is known that genetic factors play a preponderant role in stereoselectivity; however, the influence of diseases has been surprisingly little investigated.
Patients with reduced renal function may present changes in metabolism, which may be induced or inhibited.20-22 Considerable increase in antipyrine and nifedipine clearance probably due to induction of CYP3A was observed in an investigation of hypertensive patients with moderate renal failure.21 Reduced activity of the CYP3A in patients with end-stage renal disease who were undergoing long-term hemodialysis 3 times a week was reported by Dowling et al.20 Renal failure does not alter the elimination half-life or the total clearance of metoprolol because of the low renal excretion (10%) and the low binding to plasma proteins (12%) of the drug.3 Nonstereoselective studies have demonstrated that chronic renal failure (CRF) results in prolonged elimination half-life and plasma accumulation of the active OHM metabolite and total metabolites.12
There are no data available about the influence of CRF on the individual metabolic pathways of metoprolol. Thus, the aim of the present study was to investigate the influence of CRF on the stereoselective metabolism of metoprolol in hypertensive patients under treatment with the beta-blocker in an oral multiple-dose regimen. The complete stereoselective metabolism of metoprolol in hypertensive patients is also reported.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Debrisoquine Phenotype
On the morning of the debrisoquine test, the patients received a single oral dose of 10 mg debrisoquine (Debrisoquine, Cambridge Laboratories, England) after spontaneous complete bladder emptying and a 12-hour fast. Urine was collected up to 8 hours after the administration of the probe drug and then homogenized. The volume was recorded, and an aliquot of approximately 10 mL was stored at -20°C until analysis. Patients with debrisoquine/4-hydroxydebrisoquine metabolic ratios higher than 12.6 were classified as poor metabolizer phenotypes25 and excluded from the study.
CYP2D6 Genotype
EDTA blood samples were drawn and DNA was isolated using a whole-blood DNA extraction kit (Genomic Prep Blood DNA Isolation Kit, Amersham Biosciences, Piscataway, NJ). Genotyping was performed by allele-specific amplification of mutant CYP2D6 alleles as described by Heim and Meyer.26 This PCR allows the detection of the frameshift mutation of CYP2D6*3 and the splice-site mutation of CYP2D6*4.
Metoprolol Metabolism
Patients had all antihypertensive therapy discontinued 1 week before the study period (washout period). Drugs used during the study are listed in Table I. After the washout period, patients were treated with rac-metoprolol tartrate (Seloken, Astra, Brazil) in a multiple-dose schedule (2 tablets of 100 mg once daily) for 7 days, because previous studies demonstrated that steady state is reached after 5 days of administration.10 All hypertensive patients had blood pressure not exceeding 180/110 mm Hg at the end of the washout period. On the seventh day of medication administration, they were admitted to the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and received the daily dose of rac-metoprolol with 200 mL of water under fasting conditions. A standard hospital diet was served 4 hours after metoprolol administration. Serial blood samples were collected with heparinized syringes (Liquemine, 5000 IU, Roche, Brazil) at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, and 36 hours after metoprolol administration. Plasma samples obtained after centrifugation for 20 minutes at 1800g were stored at -20°C. Urine was collected at 6-hour intervals up to 36 hours after administration of the drug. During the study period, the patients were not allowed to take drugs known to inhibit CYP2D6.
Analytical Methods
Debrisoquine and its metabolite, 4-hydroxydebrisoquine, were analyzed in urine by high-performance liquid chromatography (HPLC) with fluorescence detection according to a previously described method.27 The isomers of metoprolol and OHM were resolved simultaneously with a normal-phase HPLC system using a Chiralpak AD column and fluorescence detection.28,29 The quantification limit obtained was 2.0 ng/mL plasma and 0.125 µg/mL urine for individual OHM isomers. Metoprolol acid metabolite was analyzed in plasma and urine samples with a reverse-phase HPLC system using a Chiralcel OD-R column and fluorescence detection.30 The quantification limit obtained was 17.0 ng/mL plasma and 0.5 µg/mL urine for each enantiomer. Both methods were validated with intra- and interday variations of less than 15%.
Pharmacokinetic Analysis
The pharmacokinetic evaluation was carried out by means of the pharmacokinetic software PK Solutions. The stereoselective kinetic disposition of metoprolol, MAM, and OHM was calculated within 1 time-dosing interval, with metoprolol plasma concentrations data better described by a 2-compartment open model and metabolites data better described by a 1-compartment model. Peak plasma concentration (Cmax) and tmax were obtained from the raw data of the individual patients. Terminal half-life (t1/2ß) was calculated based on the log plasma concentration curves as a function of collection time, and elimination rate constant (ß) was obtained using the ß = 0.693/t1/2ß. Area under the plasma concentration-time curve (
) and metoprolol total clearance (
) were determined as described previously.31 Renal clearance (ClR) was calculated by dividing the amount of each unchanged isomer recovered in urine over 24 hours by its . The apparent eliminated dose fraction (Fel/f) was calculated by dividing the metoprolol dose (corrected by the molecular weight of MAM or OHM for metabolite calculation) by the amount of each isomer recovered in 24-hour urine. The partial clearance of MAM and OHM formation (ClM/f) was calculated by multiplying the apparent total metoprolol clearance by the apparent eliminated dose fraction (Fel/f) of each isomer in 24 hours.
To construct metabolic ratio curves, plasma concentrations of OHM isomers and MAM enantiomers were divided by the plasma concentration of the corresponding metoprolol enantiomer at each collection time.
Statistical Analysis
The data are presented as means and 95% confidence intervals (CIs) and as medians and CIs in case of non-Gaussian distribution. The paired Wilcoxon test was used to analyze metoprolol and MAM enantiomer ratios differing from 1. OHM isomeric ratios were analyzed by repeated-measures analysis of variance (ANOVA), and the Tukey-Kramer posttest was applied for multiple comparisons. The Mann-Whitney unpaired test was used to compare control and CRF data. The level of significance was set at 5% in all statistical tests. The Spearman test ( = 0.05) was used to analyze the correlation between debrisoquine phenotype and metoprolol -hydroxylation, employing the metabolic debrisoquine/4-hydroxydebrisoquine ratio versus the 3-hour plasma metoprolol/OHM concentration.32
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The mean curves for the plasma concentrations of metoprolol and its metabolites versus time are presented in Figure 2. The pharmacokinetic parameters represented by the mean or median and 95% confidence interval are presented in Tables II, III, IV and V.
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In the control group, the pharmacokinetic parameters of metoprolol showed that the plasma concentration versus time curves for (R)- and (S)-metoprolol presented the same decay, with no statistically significant difference in elimination half-life (t1/2ß) or elimination rate constant (ß) (Table II; Figure 2a). The values of Cmax, , ClT/f, Ae, and Fel/f presented statistically significant differences between the enantiomers of metoprolol in the control group, confirming the occurrence of enantioselectivity in the pharmacokinetics of metoprolol.5,8,18 The observation of higher areas under the plasma concentration versus time curves () for (S)-metoprolol compared to its antipode (P < .05) was the consequence of a lower ClT/f for this enantiomer and resulted in mean AUC(S)-/AUC(R)- ratios of 1.21.
The formation of the OHM metabolite proved to be stereoselective in the control group, favoring the formation of the new chiral center 1'R, regardless of the configuration of the chiral center of the propanolamine chain (Figure 2b). Tables III and IV show a statistically significant difference (P < .05) between the 1'S and 1'R isomers for the parameters Cmax, , Ae0-24, Fel/f, and ClM, greatly favoring the 1'R isomers (AUC1'R/AUC1'S= 2.37). The mean curves for the metabolic ratios 2R-OHM/(R)-metoprolol and 2S-OHM/(S)-metoprolol in plasma samples versus time are presented in Figure 3a.
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, Cmax, and ClM for this enantiomer (AUC(S)-/AUC(R)- = 0.81). The mean curves for the metabolic ratios (R)-MAM/(R)-metoprolol and (S)-MAM/(S)-metoprolol in plasma samples versus time are presented in Figure 3b. The CRF group presented stereoselectivity in metoprolol metabolism closely similar to that observed in the control group, with plasma accumulation of (S)-metoprolol (AUC(S)-/AUC(R)- = 1.24; Table II; Figure 2a). The formation of the OHM (AUC1'R/AUC1'S= 2.87; AUC2S/AUC2R = 1.27; Tables III-IV; Figure 2b) and MAM (AUC(S)-/AUC(R)- = 0.91; Table V; Figure 2c) metabolites followed the same pattern as observed in the control group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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-hydroxymetoprolol, and metoprolol acidic metabolite were evaluated at steady state after oral administration of 200 mg rac-metoprolol tartrate once daily. Metoprolol was administered to the patients only by the oral route, a fact that prevented the determination of bioavailability. Although previous studies have fixed the bioavailability of racemic metoprolol at 38% ± 14%,3 the pharmacokinetic parameters depending on bioavailability, such as clearance and eliminated dose fraction, are calculated in a more precise manner as apparent parameters (ie, ClT/f and Fel/f) because there are no data about the bioavailability of the isolated enantiomers.1
Intra- and interindividual variability in the pharmacokinetics of metoprolol is mainly due to the activity of the polymorphic CYP2D6.18,33 The investigated patients were submitted to the debrisoquine test, considering that only the CYP2D6 extensive metabolizers demonstrate enantioselectivity in the kinetic disposition of metoprolol and in the formation of OHM.14,18 Debrisoquine phenotype can be determined using the metabolic ratio or the recovery ratio of debrisoquine in urine as an index of CYP2D6 activity. Kaisary et al34 showed that the recovery ratio is proportional to CYP2D6 activity and is better related to the formation of 4-hydroxydebrisoquine. However, Rostami-Hodjegan et al35 suggest that the metabolic ratio of debrisoquine should be preferentially used in patients with CRF because the urinary recovery ratio is more sensitive to phenotyping errors due to changes in renal function. Thirteen out of 15 patients studied presented metabolic debrisoquine/4-hydroxydebrisoquine ratios lower than 12.6 and were therefore phenotyped as CYP2D6 extensive metabolizers (Table I). The statistically significant correlation existing between the urinary metabolic debrisoquine/4-hydroxydebrisoquine ratio and the 3-hour plasma metoprolol/OHM ratio in the investigated patients (r = 0.9246, Spearman test) confirms that the 2 metabolic pathways are essentially controlled by the same enzyme (CYP2D6) and shows that both debrisoquine and metoprolol can be used as CYP2D6 drug markers for self-reported white Brazilians. The correlation between the -hydroxylation of metoprolol and the 4-hydroxylation of debrisoquine was also observed in British, Japanese, and Turkish populations.32,36,37 In Nigerian and South African populations, however, poor debrisoquine metabolizers were not phenotyped as poor metoprolol metabolizers.19
The results showed enantioselectivity in the pharmacokinetics of metoprolol, with observation of higher areas under the plasma concentration versus time curves for (S)-metoprolol compared to its antipode (P < .05) as consequence of a lower ClT/f for this enantiomer, and resulted in mean AUC(S)-/AUC(R)- ratios of 1.21. Enantiomeric ratios of 1.39 were reported by Johnson and Burlew5 in the investigation of healthy volunteers treated with a single dose of racemic metoprolol, and ratios of 1.29 were reported by Cerqueira et al8 in a study of multiple doses of racemic metoprolol administered to hypertensive patients with the EM debrisoquine phenotype.
The formation of -hydroxymetoprolol was stereoselective, favoring the 1'R chiral center. This result agrees with literature studies on human liver microsomes.14,16 The cited studies also demonstrated preferential -hydroxylation of the (S)-metoprolol enantiomer. In the present study, we observed AUC2S/AUC2R ratios higher than 1 (AUC2S/AUC2R = 1.22), although there was no significant difference between the pharmacokinetic parameters of the 2R and 2S enantiomers (Tables III-IV).
Metoprolol acidic metabolite formation presented enantioselectivity, favoring the formation of (R)-MAM (AUC(S)-/AUC(R)- = 0.81). Previous studies on human liver microsomes14,16 and in healthy volunteers treated with an oral solution of rac-metoprolol also indicated a preferential formation of (R)-MAM (AUC(S)-/AUC(R)- = 0.85).38 O-Demethylation is the main metabolic pathway for metoprolol, about 65% of the dose, whereas -hydroxylation accounts for no more than 10% of the elimination. The enantioselectivity in metoprolol pharmacokinetics and in MAM formation, favoring (R)-enantiomer formation for the control and CRF groups, suggests that O-demethylation is the metabolic pathway responsible for (S)-metoprolol accumulation in the plasma of hypertensive patients phenotyped as CYP2D6 extensive metabolizers.
Because of the low renal excretion of unchanged metoprolol (<10%) and the low binding of the drug to plasma proteins, no significant differences in pharmacokinetic metoprolol parameters were observed between the control and CRF groups (Table II). Several studies have demonstrated that the metabolic clearance of various drugs is reduced among patients with CRF and that the disease is associated with a decrease in intestinal drug metabolism (mainly CYP1A1 and CYP3A2) in rats.22 However, our results suggest that the stereoselective metabolism of metoprolol was affected by CRF without reduction of the metoprolol metabolic clearance of OHM and MAM (Figure 2; Tables II, IV, and V).
Patients with CRF presented higher plasma concentrations of the 4 OHM isomers, as demonstrated by Cmax and values approximately 2.5 times higher than those observed in the control group (Table III). This accumulation may be attributed in part to the reduction in renal clearance. However, an 
40% reduction in ClR does not explain the 2- to 3-fold plasma accumulation of OHM in this group. Thus, we may suggest that the accumulation of OHM in CRF patients was mainly due to changes in metoprolol metabolism. The plasma accumulation of the acid metabolite in the CRF group (Figure 2c and Table V) probably shifts the equilibrium of the enzymatic ratios by favoring the metoprolol available for -hydroxylation, thus explaining the accumulation of OHM, which does not depend on CYP2D6 induction.
The curves for the ratios of plasma 2R-OHM/(R)-metoprolol and 2S-OHM/(S)-metoprolol concentrations versus time (Figure 3a) show a decrease in the ratios as a function of metoprolol absorption (0-1 hours) and, starting from this point, a progressive increase, which may be interpreted as OHM formation and metoprolol elimination at a faster rate than OHM elimination. The control and CRF groups showed curves with the same profile but with higher ratios in the CRF group due to higher plasma concentrations of OHM. Based on the fact that the CYP2D6 responsible for this metabolic pathway is not induced under any circumstances, changes in other metabolic pathways of metoprolol must explain the changes observed in the CYP2D6-dependent -hydroxylation.
Metoprolol acidic metabolite formation depends on CYP2D6 and other enzymes, including intestinal CYP3A, which differ from CYP2D6 by their enantioselectivity and low affinity for the substrates.13,14 Comparison of the kinetic disposition of MAM between the control and CRF groups showed that CRF patients accumulate both enantiomers of the acid metabolite, as demonstrated by the higher and Cmax values (Table V). This accumulation may be attributed in part to the reduction in urinary elimination rate constant and renal excretion (ClR) in the CRF group. However, a 50% reduction in ClR does not explain the 3- to 4-fold plasma accumulation of MAM in this group, suggesting that metoprolol metabolism is affected in this disease in addition to renal excretion. The curves of the ratios of plasma concentrations of (R)-MAM/(R)-metoprolol and (S)-MAM/(S)-metoprolol versus time for the control group (Figure 3b, left) showed a decrease in the ratios at the beginning (metoprolol absorption; 0-30 minutes), a progressive increase during the phase of formation of the acid metabolite (up to 3 hours), and then a new decrease until the end of the dose interval (24 hours), explained by the elimination of the acid metabolite at a faster rate than metoprolol elimination (Kel MAM/ß metoprolol 3; Tables II and V). The profile of the curve for the CRF group (Figure 3b, right) was quite different from that observed for the control group. After the decrease during the phase of metoprolol absorption, there was a progressive increase of the ratios until the end of the dose interval. The elimination rate constants for metoprolol and MAM were closely similar in the CRF group (
0.095 h-1; Tables II and V), thus leaving this increase unexplained. Based on the plasma accumulation of MAM higher than the reduction of ClR in the CRF group, we suggest that the induction of the CYP isoform is responsible for the formation of the acidic metabolite in patients with CRF. Metoprolol acidic metabolite formation depends on CYP2D6, which cannot be induced, and other enzymes, including intestinal CYP3A. Additional studies, including CYP3A markers, are required to clarify the mechanism of plasma metoprolol metabolites accumulation in patients with moderate chronic renal failure because CYP3A induction has been previously reported in patients with CRF.21
The accumulation of OHM and MAM observed in patients with chronic renal failure must not influence the beta-blocker effect of metoprolol. OHM is considered to be an active metabolite, but its beta-blocker action has been reported to be only 1/10 of the activity of metoprolol when the 2 drugs are compared regarding their effect on heart rate reduction during exercise.39 Nevertheless, the present study shows that chronic renal failure is accompanied by changes in the activity of CYP3A, which is involved in the metabolism of a larger number of drugs. Thus, studies using other medications metabolized through this pathway are needed to assess the clinical impact of this finding.
In conclusion, metoprolol metabolism is stereoselective in hypertensive patients treated with rac-metoprolol in a multiple-dose schedule. The presence of CRF does not change the pharmacokinetics of unchanged metoprolol but modifies its stereoselective metabolism without inducing CYP2D6 but inducing some of the CYP enzymes responsible for MAM formation. The data suggest that CRF can modify the activity of CYP enzymes and change the stereoselective metabolism of other drugs.
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