The influence of edema on the bisoprolol blood concentration after bisoprolol dermal patch application: A case-control study.

BACKGROUND: Beta-blocking is important for critically ill patients. Although some patients are required to continue taking beta-blockers after they no longer need critical care, some of these patients have impaired swallowing abilities. Bisoprolol dermal patches have recently been introduced and appear to be a good alternative to oral bisoprolol tablets. However, it is still unclear whether the pharmacodynamics of such patches are affected by edema in patients who have experienced critical care. This study aimed to clarify the effects of systemic edema on beta-blocker absorption from dermal patches in critically ill patients. METHOD: Patients who exhibited tachycardia and impaired swallowing function after critical care were included in this study. They were assigned to either the edema group (n = 6) or no edema group (n = 6) depending on the presence/absence of edema in the lower extremities. A bisoprolol dermal patch was pasted onto each subject, and the blood bisoprolol concentration was checked at 8 timepoints over the next 24 hours. The area under the serum concentration time curve, maximum concentration observed (Cmax), and time of maximum concentration observed were also examined. RESULT: The mean blood bisoprolol concentrations of the 2 groups were not significantly different at 2, 4, 6, 8, 10, 12, 16, or 24 hours after the patch application. The area under the serum concentration time curve and maximum concentration observed were not different between the groups. The mean heart rates of the 2 groups were not significantly different at 6, 12, or 24 hours after the patch application (Student t test, P = .0588, P = .1080, and P = .2322, respectively). CONCLUSION: In this study, the blood concentration of bisoprolol and its heart rate-reducing effects after bisoprolol dermal patch application might not be affected by systemic edema in the lower extremities.

Highly exfoliated functionalized MoS2 with sodium alginate-polydopamine conjugates for electrochemical sensing of cardio-selective ß-blocker by voltammetric methods.

Molybdenum disulfide (MoS2) surface functionalization was performed with a catechol-containing polymer sodium alginate (SA) and dopamine (DA) through simultaneous MoS2 exfoliation and self-polymerization of DA. The MoS2/SA-PDA nanocomposite was characterized using spectroscopic, microscopic, and electroanalytical techniques to evaluate its electrocatalytic performance. The electrocatalytic behavior of the MoS2/SA-PDA nanocomposite modified electrode for the detection of acebutolol (ACE), a cardio-selective ß-blocker drug was explored  through cyclic voltammetric and differential pulse voltammetric techniques. The influence of scan rate, concentration, and pH value on the oxidation peak current of ACE was investigated  to optimize the deducting condition. The electrochemical activity of the MoS2/SA-PDA nanocomposite electrode was attributed to the existence of reactive functional groups being contributed from SA, PDA, and MoS2 exhibiting a synergic effect. The MoS2/SA-PDA nanocomposite modified electrode exhibits admirable electrocatalytic activity with a wide linear response range (0.009 to 520 µM), low detection limit (5 nM), and high sensitivity (0.354 µA µM-1 cm-2) also in the presence of similar (potentially interfering) compounds. The fabricated MoS2/SA-PDA nanocomposite modified electrode can be useful for the detection of ACE in pharmaceutical analysis.

Association Between Dose and Plasma Concentration of Bisoprolol in Patients with Heart Failure (CVI ARO 6).

Although bisoprolol is used widely to treat patients with heart failure (HF), little information is available regarding the association between the dose of bisoprolol administered and the bisoprolol plasma concentration (Bis-PC) in real-world clinical practice.This was a single-center, observational study in 114 patients with HF receiving once-daily bisoprolol. After determination of trough Bis-PC, the relationship between the dose of bisoprolol and Bis-PC was analyzed. In a multiple linear regression model, the dose of bisoprolol and estimated creatinine clearance (reciprocal number) were identified as independent predictors. HF severity and hepatic function were not associated with Bis-PC.Bis-PC was increased by renal dysfunction, which explained most of the discrepancy between the dose of bisoprolol administered and Bis-PC.

Effect of Roux-en-Y gastric bypass on the bioavailability of metoprolol from immediate and controlled release tablets: a single oral dose study before and after surgery.

Objective: Roux-en-Y gastric bypass (RYGB) surgery induces major changes in the gastrointestinal tract that may alter the pharmacokinetics of orally administered drugs. Results from pharmacokinetic studies are sparse. This study aimed to investigate the effect of RYGB on the bioavailability of metoprolol from immediate release (IR) and controlled release (CR) tablets in female patient volunteers before and after surgery. Methods: An explorative, two-phase, single oral dose pharmacokinetic study of metoprolol in female patients undergoing RYGB was carried out. The dose was administered twice in each patient, 1 month before and 6 months after surgery. After intake of either 100 mg of metoprolol IR or CR tablet serum concentration-time profiles of metoprolol were determined. The endpoint was the ratio of AUCafter/AUCbefore of metoprolol. Results: Twelve patients were included in the study (metoprolol IR: 7; metoprolol CR: 5). After intake of a metoprolol IR tablet major intraindividual and interindividual differences for area under the serum concentration versus time curve (AUC) of metoprolol before and after surgery were observed (range ratio AUC0-10 hours after/AUC0-10 hours before: 0.74-1.98). For metoprolol CR tablets a significant reduction in bioavailability of metoprolol was observed after surgery (range ratio AUC0-24 hours after/AUC0-24 hours before: 0.43-0.77). Conclusion: RYGB may influence the bioavailability of metoprolol from an IR tablet. The magnitude of changes in bioavailability after RYGB requires close monitoring of patients using metoprolol IR tablets and dose adjustment if deemed necessary. RYGB clearly reduces the bioavailability of metoprolol from a CR tablet. After RYGB clinicians may consider to increase the dose according to clinical response.

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study.

PURPOSE: The ß-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). METHODS: We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200 mg/day within 2 months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. RESULTS: According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p < 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p < 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2 bpm, p < 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. CONCLUSION: Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome.

To date, many questions about the extent and cause of pharmacokinetic (PK) variability of even the most widely studied and prescribed ß1-adrenergic receptor blockers, such as metoprolol and bisoprolol, remain unanswered. Given that there are still no published population pharmacokinetic (PopPK) analyses of bisoprolol in routinely treated patients with acute coronary syndrome (ACS), the aim of this study was to determine its PK variability in 71 Serbian patients with ACS. PopPK analysis was conducted using a nonlinear mixed-effects model (NONMEM), version 7.3.0 (Icon Development Solutions). In each patient, the same formulation of bisoprolol was administered once or twice daily at a total daily dose of 0.625-7.5 mg. We separately assessed the effects of 31 covariates on the PKs of bisoprolol, and our results indicated that only 2 covariates could have possible influence on the variability of the clearance of bisoprolol: the mean daily dose of the drug and smoking habits of patients. These findings suggest that possible autoinduction of drug metabolism by higher total daily doses and induction of cytochrome P450 isoform 3A4 (CYP3A4) by cigarette smoke in liver could be the potential causes of increased total clearance of bisoprolol in patients with ACS.

How do different extracorporeal circulation systems affect metoprolol bioavailability in coronary artery bypass surgery patients.

PURPOSE: Cardiac surgery and conventional extracorporeal circulation (CECC) impair the bioavailability of drugs administered by mouth. It is not known whether miniaturized ECC (MECC) or off-pump surgery (OPCAB) affect the bioavailability in similar manner. We evaluated the metoprolol bioavailability in patients undergoing CABG surgery with CECC, MECC, or having OPCAB. METHODS: Thirty patients, ten in each group, aged 44-79 years, scheduled for CABG surgery were administered 50 mg metoprolol by mouth on the preoperative day at 8-10 a.m. and 8 p.m., 2 h before surgery, and thereafter daily at 8 a.m. and 8 p.m. Blood samples were collected up to 12 h after the morning dose on the preoperative day and on first and third postoperative days. Metoprolol concentration in plasma was analyzed using liquid chromatography-mass spectrometry. RESULTS: The absorption of metoprolol was markedly reduced on the first postoperative day in all three groups, but recovered to the preoperative level on the third postoperative day. The geometric means (90% confidence interval) of AUC0-12 on the first and third postoperative days versus the preoperative day were 44 (26-74)% and 109 (86-139)% in the CECC-group, 28 (16-50)% and 79 (59-105)% in the MECC-group, and 26 (12-56)% and 96 (77-119)% in the OPCAB-group, respectively. Two patients in the CECC-group and two in the MECC-group developed atrial fibrillation (AF). The bioavailability and the drug concentrations of metoprolol in patients developing AF did not differ from those who remained in sinus rhythm. CONCLUSION: The bioavailability of metoprolol by mouth was markedly reduced in the early phase after CABG with no difference between the CECC-, MECC-, and OPCAB-groups.

Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples.

BACKGROUND: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. METHODS: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. RESULTS: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. CONCLUSION: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Lethal suicide attempt with a mixed-drug intoxication of metoprolol and propafenone - A first pediatric case report.

INTRODUCTION: The ß1 adrenergic receptor blocker metoprolol is often prescribed together with the antiarrhythmic drug propafenone. Both are metabolized by cytochrome P450 2D6 and propafenone is also an inhibitor of this enzyme. We present a pediatric case showing metoprolol and propafenone intoxication in combination. CASE: A 14-year-old girl was admitted to a local emergency department after ingestion of metoprolol (probably 1g) and propafenone (probably 1.5-3g) in a suicide attempt. She developed cardiogenic shock with cardiac arrest and was fully resuscitated. Veno-arterial femorofemoral extracorporeal membrane oxygenation was started immediately. High serum levels of both drugs were detected approximately 10h after ingestion (2630ng/mL metoprolol and 2500ng/mL propafenone). Other serial samples for the monitoring of the levels of metoprolol and its metabolite alfa-hydroxymetoprolol were obtained between days 2 and 4 after admission. The metoprolol/alfa-hydroxymetoprolol ratio on the 2nd day was 36.1, indicative of a poor metabolizer phenotype. The elimination half-life of metoprolol was prolonged to 13.2h and the clearance decreased by about 70%. The patient condition gradually worsened, brain edema and intracerebral hemorrhage occurred, and on the 6th day, the patient died. CONCLUSION: We document a pediatric case report of death due to a mixed drug overdose of metoprolol and propafenone, along with data regarding serum metoprolol, alfa-hydroxymetoprolol, and propafenone levels.

Metoprolol decreases the plasma exposure of metformin via the induction of liver, kidney and muscle uptake in rats.

Drug interactions are one of the commonest causes of side effects, particularly in long-term therapy. The aim of the current study was to investigate the possible effects of metoprolol on the pharmacokinetics of metformin in rats and to clarify the mechanism of drug interaction. In this study, rats were treated with metformin alone or in combination with metoprolol. Plasma, urine and tissue concentrations of metformin were determined by HPLC. Western blotting and real-time qPCR were used to evaluate the expression of rOCTs and rMATE1. The results showed that, after single or 7-day repeated administration, the plasma concentrations of metformin in the co-administration group were significantly decreased compared with that in the metformin group. However, the parameter V/F of metformin in the co-administration group was markedly increased compared with that in the metformin group. The hepatic, renal and muscular Kp of metformin were markedly elevated after co-administration with metoprolol. Consistently, metformin uptake in rat kidney slices was significantly induced by metoprolol. In addition, multiple administrations of metoprolol significantly reduced the expression of rMATE1 in rat kidney as well as the urinary excretion of metformin. Importantly, after long-term administration, lactic acid and uric acid levels in the co-administration group were increased by 25% and 26%, respectively, compared with that in the metformin group. These results indicate that metoprolol can decrease the plasma concentration of metformin via the induction of hepatic, renal and muscular uptake, and long-term co-administration of metformin and metoprolol can cause elevated lactic acid and uric acid levels. Copyright © 2016 John Wiley & Sons, Ltd.

Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate.

Computational design and multivariate optimization of an electrochemical metoprolol sensor based on molecular imprinting in combination with carbon nanotubes.

This work describes the development of an electrochemical sensor based on a new molecularly imprinted polymer for detection of metoprolol (MTP) at ultra-trace level. The polypyrrole (PPy) was electrochemically synthesized on the tip of a pencil graphite electrode (PGE) which modified whit functionalized multi-walled carbon nanotubes (MWCNTs). The fabrication process of the sensor was characterized by cyclic voltammetry (CV) and the measurement process was carried out by differential pulse voltammetry (DPV). A computational approach was used to screening functional monomers and polymerization solvent for rational design of molecularly imprinted polymer (MIP). Based on computational results, pyrrole and water were selected as functional monomer and polymerization solvent, respectively. Several significant parameters controlling the performance of the MIP sensor were examined and optimized using multivariate optimization methods such as Plackett-Burman design (PBD) and central composite design (CCD). Under the selected optimal conditions, MIP sensor was showed a linear range from 0.06 to 490 µmol L(-1) MTP, a limit of detection of 2.88 nmol L(-1), a highly reproducible response (RSD 3.9%) and a good selectivity in the presence of structurally related molecules. Furthermore, the applicability of the method was successfully tested with determination of MTP in real samples (tablet, and serum).

Bisoprolol pharmacokinetics and body composition in patients with chronic heart failure: a longitudinal study.

PURPOSE: We investigated bisoprolol pharmacokinetics, including longitudinal changes and importance of patient characteristics in chronic heart failure. METHODS: Forty-six patients with chronic heart failure (57 % male, NYHA class I/II/III = 2/36/8) were followed for an average of 8 ± 2 months. At baseline and follow-up, plasma bisoprolol concentrations were determined and body composition was measured using dual-energy X-ray absorptiometry. A bisoprolol pharmacokinetic model was built with non-linear mixed-effects modeling to analyze the association with various parameters of body composition. RESULTS: Mean bisoprolol clearance (10.2 L/h) was 30 % lower than in healthy individuals and correlated with MDRD4-estimated renal function. The mean volume of distribution (230 L) was similar to healthy population and was associated with total body mass and skeletal muscle index (SMI). During follow-up, we observed minor changes in the absorption rate constant (2.83 vs. 2.27 h(-1), P = 0.030) and volume of distribution (227 vs. 250 L, P = 0.004), which are not clinically relevant. CONCLUSIONS: In patients with chronic heart failure, bisoprolol clearance was associated with estimated renal function; thus, in moderately and severely decreased renal function, patients may need to have their dose adjusted. Patients with low body weight or low SMI have greater fluctuations and higher maximal plasma concentrations of bisoprolol because of the lower volume of distribution. Longitudinal changes of bisoprolol pharmacokinetics were not associated with changes in body composition.

Population Pharmacokinetics of Bisoprolol in Hemodialysis Patients with Hypertension.

The aim of our study was to estimate clearance of bisoprolol and reveal the factors that could influence its pharmacokinetic (PK) variability in hypertensive patients on hemodialysis, using the population PK analysis. Parameters associated with plasma concentration of bisoprolol at steady state were analyzed in 63 patients (mean age 62.12 years, mean total weight 69.63 kg) who were hypertensive and on hemodialysis due to severe renal failure using non-linear mixed-effect modeling with ADVAN1 subroutine. The final regression model for the clearance of the drug included only creatinine clearance (CLcr) out of 12 tested covariates. The equation that describes CL of bisoprolol is the following: CL (l/h) = 0.12 + 6.33 * CLcr. These findings suggest that the routine measuring of serum creatinine level may be used to facilitate administration of bisoprolol in patients on hemodialysis.

Preparation of bisoprolol fumarate nasal spray and its nasal delivery in rats.

The aim of the present work was to prepare a nasal spray of bisoprolol fumarate (BF). The Pharmacokinetics and relative bioavailability of the BF nasal formulation were evaluated in Wistar rats. The BF nasal spray after administration exhibited very fast absorption and higher plasma drug concentration. The maximum plasma concentration (C(max)) and the time to reach it (T(max)) were 409.5 ng/ml and 3.6 min for the BF nasal spray, 39.4 ng/ml and 26.7 min for the drug solution, respectively. The bioavailability of the BF nasal spray was greater than 1500.0%. Meantime, the effect of the BF nasal spray on nasal mucociliary movement was also studied with a toad palate model. The BF nasal preparation showed minor ciliotoxicity, but the adverse effect was temporary and reversible.

The effect of AST-120 on the single-dose pharmacokinetics of metoprolol extended-release tablets in healthy subjects.

BACKGROUND: This was a randomized, open-label, three-way crossover study to assess the effects of AST-120 (an orally administered spherical carbon adsorbent acting in the gastrointestinal tract without systemic circulation) on the single-dose pharmacokinetics of metoprolol in an extended-release formulation (metoprolol ER) in healthy volunteers. METHODS: A total of 34 subjects were singly administered metoprolol ER alone (A), and metoprolol ER in combination with AST-120 simultaneously (B) and 1 h later (C). RESULTS: The total exposure was more significantly reduced in both treatments B and C than that in treatment A; the geometric mean ratios of area under the curve extrapolated to infinity (AUC0-∞) for B/A and C/A were reduced by approximately 30% in both treatments B and C. Maximum observed plasma concentration (Cmax) of metoprolol in treatment B significantly decreased, whereas Cmax in treatment C was slightly decreased. AST-120 treatment was unlikely to affect apparent first-order terminal elimination half-life (T1/2) of metoprolol significantly. Reduction in heart rate and blood pressure readings were similar across the treatment periods. Coadministration of AST-120 and metoprolol ER was safe and was well tolerated. CONCLUSIONS: Because AST-120 reduced gastrointestinal absorption of metoprolol ER, careful monitoring of heart rate and blood pressure is recommended in coadministration of AST-120 with metoprolol ER.

ß1-selective adrenoceptor antagonists increase plasma levels of anti-p2ß antibodies and decrease cardiac involvement in chronic progressive Chagas heart disease.

BACKGROUND: Studies indicate that antibodies cross-reacting with cardiac ß1 adrenergic receptors are likely to play a role in the development of chronic Chagas heart disease (CCHD). In parallel, clinical trials have shown that ß1 antagonist drugs exert beneficial effects in the prognosis of patients with CCHD. In a group of patients with CCHD undergoing therapy with ß1-blockers, we have now evaluated the levels of anti-p2ß antibodies and the severity of CCHD. METHODS: We performed a cross-sectional study in Trypanosoma cruzi seropositive patients categorized according to a standard CCHD classification. All individuals were subjected to a complete clinical examination. RESULTS: There was no association between CCHD stages, electrocardiographic conduction disturbances, and echocardiogram pathological signs with the levels of autoantibodies. However, when patients were analyzed according to selective cardio-ß1-blocker therapy, those receiving treatment had higher levels of anti-p2ß. Patients from CCHD stage III treated with combined therapy of cardio-ß1-selective blockers, enalapril, and statins, presented decreased cardiac involvement and lower score of risk of mortality than individuals from the same group who were not treated. CONCLUSIONS: Our results suggest that selective cardio-ß1-blockers might modify the autoantibody anti-p2ß levels, and that combined therapy in patients with stage III CCHD might be associated with lower cardiac involvement and risk score of mortality in patients with heart failure. Longitudinal studies will help to ascertain the proper role of ß1-blockers in the immunopathological processes underlying chronic Chagas disease.

Development of in vitro-in vivo correlation for encapsulated metoprolol tartrate.

This study was aimed to develop level A, B and C in vitro-in vivo correlation (IVIVC) for encapsulated metoprolol tartrate (T1, T2 and T3 having metoprolol tartrate/polymer ratio of 1: 1, 1: 1.5 and 1: 2,w/w). The in vitro data were correlated with in vivo data. For level A IVIVC, drug absorption data were calculated using Wagner-Nelson method. In addition, convolution approach was used to approximate plasma drug levels from in vitro dissolution data. The coefficient of determination (R2) for level A IVIVC was 0.720, 0.905, 0.928 and 0.878 for Mepressor, T1, T2 andT3 formulations, respectively, with acceptable percent error (< 15%). The value of R2 for level B and C IVIVC was 0.231and 0.714, respectively. It is also concluded that level A IVIVC is a proficient mathematical model for biowaiver studies involving study parameters as those implemented for T1S (T1formulation tested for dissolution in the presence of sodium lauryl sulfate) revealing that IVIVC level A is dosage form specific, rather than to be drug specific.

Faster non-renal clearance of metoprolol in streptozotocin-induced diabetes mellitus rats.

Metoprolol is a selective ß1-adrenergic receptor antagonist metabolized by hepatic cytochrome P450s (CYPs). In this study, we evaluated pharmacokinetic changes following intravenous (i.v.) and oral metoprolol in rats with diabetes mellitus induced by streptozotocin (DMIS). Metoprolol has an intermediate hepatic extraction ratio in rats (0.586-0.617), and it is assumed that the liver is exclusively responsible for metoprolol metabolism. Thus, the hepatic clearance, CL(H) (the non-renal clearance, CL(NR)) of metoprolol depends on the hepatic blood flow rate (Q(H)), the free fraction in plasma (f(p)), and in vitro hepatic intrinsic clearance, CL(int). After i.v. administration of 1.5 mg/kg metoprolol to DMIS rats, its CLNR was 40.9% faster than control animals. This could be due to a significantly faster QH because hepatic CL(int) and fp were comparable between the two groups of rats due to unchanged hepatic CYP2D activity. After oral administration of 1.5 mg/kg metoprolol to DMIS rats, gastrointestinal absorption was >99% of the oral dose for both groups, while the area under the curve (AUC) was 27.9% smaller, which could be caused by the greater hepatic metabolism seen in the i.v. study. These findings have potential therapeutic implications, assuming that the DMIS rats qualitatively reflect similar changes in patients with diabetes.