Pharmacokinetics Of Verapamil Research Articles

Evaluation of Bioenhancing Effect of Piperine and its Analogs on the Pharmacokinetics of Verapamil

A present study was undertaken to understand the impact of piperine and some of its derivatives on the bioavailability of verapamil used in the treatment of cardiac disorders. On oral administration, it undergoes fast biotransformation resulting in its low bioavailability. Its bioavailability varies between 20 and 35%. Piperine (a well-known bioenhancer) has been reported to improve the bioavailability of a wide range of structurally and therapeutically varied medicines. Hence some derivatives of piperine were synthesized and evaluated for their bioenhancing effect on verapamil. The bioenhancing effect of piperine and synthesized derivatives was investigated and compared using a validated HPLC method per USFDA guidelines. The pharmacokinetic characteristics of verapamil alone and when combined with piperine and its synthetic analogs were also investigated. When administered to wistar rats, it was discovered that verapamil bioavailability was 1.54 times higher when given with piperine and 2.42 times higher when given with morpholine derivative. The study undertaken indicates that some synthetic derivatives of piperine can be successfully used to enhance the bioavailability of verapamil to a considerable extent

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions.

To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (-54Δ%), furosemide (-20Δ%), propranolol (-8Δ%), and acetaminophen (-9Δ%), but a statistically significant increase in Vz was found for etacizine (+39Δ%); there was an increasing trend in Clt for propranolol (+13Δ%) and acetaminophen (+16Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (-22,-23 and-9Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13Δ%, respectively), propranolol and acetaminophen decreased (-5 and-12Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (-19 and-20Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26Δ%, respectively). A statistically significant decrease in AUC0-∞ (-57Δ%), Cmax (-53Δ%), relative bioavailability of acetaminophen (-52Δ%) and a sharp increase in Clt (+147Δ%), Tmax (+131Δ%) as well as a trend towards a significant decrease in T1/2 (-53Δ%), MRT (-36Δ%) and a moderate increase in Vz (+24Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions.

To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (-54Δ%), furosemide (-20Δ%), propranolol (-8Δ%), and acetaminophen (-9Δ%), but a statistically significant increase in Vz was found for etacizine (+39Δ%); there was an increasing trend in Clt for propranolol (+13Δ%) and acetaminophen (+16Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (-22,-23 and-9Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13Δ%, respectively), propranolol and acetaminophen decreased (-5 and-12Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (-19 and-20Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26Δ%, respectively). A statistically significant decrease in AUC0-∞ (-57Δ%), Cmax (-53Δ%), relative bioavailability of acetaminophen (-52Δ%) and a sharp increase in Clt (+147Δ%), Tmax (+131Δ%) as well as a trend towards a significant decrease in T1/2 (-53Δ%), MRT (-36Δ%) and a moderate increase in Vz (+24Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Lactobacillus rhamnosus induces CYP3A and changes the pharmacokinetics of verapamil in rats

Verapamil, a calcium channel blocker, has been approved as the first-line drug for treatment of angina pectoris, hypertension and supraventricular tachycardia. Lactobacillus rhamnosus, one of the normal strains in human intestinal tract, is very popular in the probiotic market for conferring a health benefit on the host. This report investigated the potential of gut microbiota-drug interactions between lactobacillus rhamnosus and verapamil via using wild type (WT) and Cyp3a1/2 knockout (KO) rats. In WT rats, administration of Lactobacillus rhamnosus for 14 days decreased systemic exposure of verapamil and increased its metabolite norverapamil in vivo, and resulted in gut microbiota-drug interactions. In Cyp3a1/2 KO rats, however, this interaction disappeared. Further studies found that Lactobacillus rhamnosus induced CYP3A activity and expression, and changed the composition of gut microbiota, thus changing the pharmacokinetics of verapamil. These results demonstrated the interaction between lactobacillus rhamnosus and verapamil, and indicated that the effect of gut microbiota on metabolic enzymes cannot be ignored.

A Mechanistic, Enantioselective, Physiologically Based Pharmacokinetic Model of Verapamil and Norverapamil, Built and Evaluated for Drug-Drug Interaction Studies.

The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug–drug interaction (DDI) studies as a moderate clinical CYP3A4 index inhibitor and as a clinical Pgp inhibitor. The purpose of the presented work was to develop a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to investigate and predict DDIs with verapamil. The model was established in PK-Sim®, using 45 clinical studies (dosing range 0.1–250 mg), including literature as well as unpublished Boehringer Ingelheim data. The verapamil R- and S-enantiomers and their main metabolites R- and S-norverapamil are represented in the model. The processes implemented to describe the pharmacokinetics of verapamil and norverapamil include enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific Pgp transport, and passive glomerular filtration. To describe the auto-inhibitory and DDI potential, mechanism-based inactivation of CYP3A4 and non-competitive inhibition of Pgp by the verapamil and norverapamil enantiomers were incorporated based on in vitro literature. The resulting DDI performance was demonstrated by prediction of DDIs with midazolam, digoxin, rifampicin, and cimetidine, with 21/22 predicted DDI AUC ratios or Ctrough ratios within 1.5-fold of the observed values. The thoroughly built and qualified model will be freely available in the Open Systems Pharmacology model repository to support model-informed drug discovery and development.

Short-chain fatty acids oppositely altered expressions and functions of intestinal cytochrome P4503A and P-glycoprotein and affected pharmacokinetics of verapamil following oral administration to rats.

To investigate effects of short-chain fatty acids (SCFAs) on expressions and functions of intestinal cytochrome P4503A (Cyp3a) and P-glycoprotein (P-gp). To develop a semi-physiologically based pharmacokinetic (semi-PBPK) model for assessing their contributions. Verapamil pharmacokinetics was investigated following oral administration to rats receiving water containing 150mm SCFAs for 3weeks. Cyp3a activities in intestinal and liver mircosomes were assessed by norverapamil formation. In-situ single-pass perfusion was used to evaluate intestinal transport of verapamil and P-gp function. Functions and expressions of Cyp3a and P-gp were measured in mouse primary enterocytes following 48-h exposure to SCFAs. Contributions of intestinal P-gp and Cyp3a to verapamil pharmacokinetics were assessed using a semi-PBPK model. Short-chain fatty acids significantly increased oral plasma exposures of verapamil and norverapamil. SCFAs upregulated Cyp3a activity and expression, but downregulated P-gp function and expression in rat intestine, which were repeated in mouse primary enterocytes. PBPK simulation demonstrated contribution of intestinal Cyp3a to oral plasma verapamil exposure was minor, and the increased oral plasma verapamil exposure was mainly attributed to downregulation of intestinal P-gp. Short-chain fatty acids oppositely regulated functions and expressions of intestinal Cyp3a and P-gp. The downregulation of P-gp mainly contributed to the increased oral plasmaverapamil exposure by SCFAs.

Pharmacokinetics of Verapamil and Hemodynamic Indices during Head-down Bed Rest

The purpose of this work was to study the pharmacokinetics of the Ca ion antagonist verapamil (a single dose of 80 mg) and hemodynamics in nine volunteers with normal life activities (experiment 1) and on the second day of head-down (–8°) bed rest (experiment 2). The plasma concentration of verapamil was measured using high-performance liquid chromatography with fluorometric detection. Heart rate (HR), cardiac output (CO), stroke volume (SV) and general peripheral vascular resistance (GPVR) were measured using integral rheography according to Tishchenko (Mingograf-410, Russia); blood pressure (BP) was measured by Korotkoff sounds. Analysis of verapamil pharmacokinetics in both experiments showed identity of the averaged curve profiles that did not differ significantly. The pharmacokinetic parameters were comparable. Based on hemodynamics analysis, HR elevation 1 h after verapamil administration was the most common reaction in both experiments; a short CO rise and GPVR decrease were observed in experiment 2 1 h after administration. These hemodynamic shifts were not pathologic and did not deviate from the physiological range in healthy people; changes in verapamil pharmacokinetics were also not detected. These findings provide the grounds to recommend verapamil for rational pharmacotherapy of cardiovascular diseases that may develop in piloted space missions.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration–time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

Impact of inhalational exposure to ethanol fuel on the pharmacokinetics of verapamil, ibuprofen and fluoxetine as in vivo probe drugs for CYP3A, CYP2C and CYP2D in rats

Occupational toxicology and clinical pharmacology integration will be useful to understand potential exposure-drug interaction and to shape risk assessment strategies in order to improve occupational health. The aim of the present study was to evaluate the effect of exposure to ethanol fuel on in vivo activities of cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C and CYP2D by the oral administration of the probe drugs verapamil, ibuprofen and fluoxetine. Male Wistar rats exposed to filtered air or to 2000 ppm ethanol in a nose-only inhalation chamber during (6 h/day, 5 days/week, 6 weeks) received single oral doses of 10 mg/kg verapamil or 25 mg/kg ibuprofen or 10 mg/kg fluoxetine. The enantiomers of verapamil, norverapamil, ibuprofen and fluoxetine in plasma were analyzed by LC-MS/MS. The area under the curve plasma concentration versus time extrapolated to infinity (AUC0–∞) was calculated using the Gauss–Laguerre quadrature. Inhalation exposure to ethanol reduces the AUC of both verapamil (approximately 2.7 fold) and norverapamil enantiomers (>2.5 fold), reduces the AUC0–∞ of (+)-(S)-IBU (approximately 2 fold) and inhibits preferentially the metabolism of (−)-(R)-FLU. In conclusion, inhalation exposure of ethanol at a concentration of 2 TLV-STEL (6 h/day for 6 weeks) induces CYP3A and CYP2C but inhibits CYP2D in rats.

PBPK modeling to unravel nonlinear pharmacokinetics of verapamil to estimate the fractional clearance for verapamil N-demethylation in the recirculating rat liver preparation.

We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 μM) and preformed norverapamil (1.5 and 5 μM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation. Perfusate and bile were collected over 90 minutes, and livers were harvested at the end of perfusion for high-performance liquid chromatography analysis. After correction for the adsorption of 10%-25% dose verapamil and norverapamil onto Tygon tubing and binding to albumin and red blood cell, fitting of verapamil and formed and preformed norverapamil data with ADAPT5 revealed nonlinearity for protein binding, N-demethylation (V(max,met1)(VER --> NOR) = 96.6 ± 33.4 nmol/min; K(m,met1)(VER --> NOR) = 10.4 ± 4.1 μM), formation of other metabolites (V(max,met2(VER -->others) 288 ± 51 nmol/min; K(m.met2)(VER -->others )= 14.1 ± 4.9 μM), as well as biliary excretion (V(max,sec)(VER)= 0.911 ± 0.505 nmol/min; K(m,sec)(VER) = 4.75 ± 2.29 μM). The hepatic clearance of verapamil (CL(L)(VER) decreased with the dose (8.16-10.2 ml/min), with values remaining high relative to perfusate blood flow rate among the doses. The hepatic clearance of preformed norverapamil (11 ml/min) remained unchanged for the concentrations studied and approximated perfusate blood flow rate, suggesting a high norverapamil extraction ratio. The fractional formation of norverapamil and biliary excretion of verapamil based on fitted constants were 31.1% and 0.64% of CL(L)(VER), respectively. Enantiomeric disposition and auto-inhibition of verapamil failed to perturb these estimaties according to PBPK modeling, due to the low values of the Michaelis-Menten constant, Km, and inhibition parameter, kI.

A semi-physiologically-based pharmacokinetic model characterizing mechanism-based auto-inhibition to predict stereoselective pharmacokinetics of verapamil and its metabolite norverapamil in human

Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240mg once daily). The predicted accumulation ratio was about 1.3–1.5 fold, which was close to the observed data of 1.4–2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug–drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.

Pharmacokinetics of verapamil and its metabolite norverapamil in rats with hyperlipidaemia induced by poloxamer 407

In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10 mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats).The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats.The AUC of norverapamil and AUCnorverapamil/AUCverapamil ratios following intravenous and oral administration of verapamil were unchanged in HL rats.Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.

Nonlinear Pharmacokinetics of Oral Quinidine and Verapamil in Healthy Subjects: A Clinical Microdosing Study

Microdosing studies are effective in enabling the early identification of the pharmacokinetic properties of compounds administered to humans. However, the nonlinearity of the pharmacokinetics between microdose and therapeutic dose, attributable to the saturation of metabolic enzymes and transporters, is a major concern. Verapamil and quinidine are good substrates of both the multidrug resistance 1 transporter (MDR1) and the cytochrome P450 (CYP) 3A4 enzyme (CYP3A4). We investigated their dose-dependent pharmacokinetics in healthy subjects. Four different doses of verapamil or quinidine were administered orally to each subject, and the plasma concentrations of the parent drugs and their major metabolites were measured. The dose-normalized area under the plasma concentration-time curve (AUC) values of quinidine and verapamil increased in a dose-dependent manner and were 2.6- and 2.3-fold higher, respectively, at the therapeutic dose than at microdose. These results suggest that the nonlinear pharmacokinetics of these drugs is caused mainly by the saturation of MDR1 and/or CYP3A4 in the small intestine.

Pharmacokinetics of verapamil in diabetic rats induced by combination of high-fat diet and streptozotocin injection

The aim of this study was to investigate effects of type 2 diabetes on the pharmacokinetics of verapamil after intravenous administration.Diabetes mellitus (DM) rats were induced by combination of high-fat diet (HFD) and streptozotocin. Plasma concentrations of verapamil in DM rats, rats fed with HFD, and control (CON) rats were measured after intravenous administration of 1 mg/kg verapamil and corresponding pharmacokinetic parameters were estimated. Area under the plasma concentration in DM rats was significantly smaller than that in CON rats.In vitro microsomal study showed that intrinsic clearance of verapamil in DM rats was significantly higher than those in CON rats. Compared to CON rats, higher intrinsic clearance was also observed in HFD rats. Western blot results demonstrated higher levels of CYP3A2 in DM and HFD rats, which was in line to activity of CYP3A.All the results gave a conclusion that diabetes may enhance metabolism of verapamil in rat, and the enhancement may partly result from induction of CYP3A.

Influence of Lignocaine on Plasma Protein Binding and Pharmacokinetics of Verapamil in Dogs

The effect of lignocaine (lidocaine) on the plasma protein binding of verapamil has been studied in-vitro and in-vivo in dogs. The binding of verapamil was ca 85%. In-vitro addition of lignocaine at therapeutic concentrations displaced verapamil from its plasma binding sites. Lignocaine in this regard was equipotent with tris(2-butoxyethyl)phosphate, suggesting an interaction at the level of alpha 1-acid glycoprotein binding sites. On in-vivo administration of 4 mg kg-1 in a bolus to dogs in which steady state concentrations of verapamil were present, the free fraction of verapamil increased transiently. During the lignocaine maintenance infusion, it then decreased to a level higher than that before administration of the local anaesthetic. The free verapamil concentrations increased suddenly upon the administration of the lignocaine loading dose, and then returned to values slightly higher than those before lignocaine. After a bolus injection of verapamil during a lignocaine infusion, the verapamil total plasma concentrations were lower than during a saline infusion, but the free concentrations were not different. The volume of distribution of verapamil was increased, whereas the blood clearance had not changed; the lignocaine infusion did not change the hepatic blood flow, as measured by indocyanine green clearance. These results show that lignocaine displaces verapamil in-vitro and in-vivo from its plasma protein binding sites, but the ensuing pharmacokinetic changes do not lead to significant changes in free verapamil concentrations.

INFLUENCE OF CHRONOTHERAPY WITH DIFFERENT ANTIHYPERTENSIVE DRUGS ON CIRCADIAN BLOOD PRESSURE PATTERN

Aim. To determine the value of different blood pressure (BP) measurement methods for arterial hypertension (HT) chronotherapy efficacy assessment. Material and methods. Two similar open, randomized, cross-over studies (morning vs evening intake) were carried out. Duration of the initial wash-out period was 2 weeks; duration of both treatment courses — 3 weeks; the interval between courses — 1 week. Only patients with stable HT (mean day-time BP>135/85 mm Hg) were included. Ambulatory BP monitoring (ABPM) was carried out prior to treatment and at the end of both treatment courses. The patients performed home BP monitoring (HBPM) throughout the study. Pharmacokinetics of verapamil (n=14, mean daily dose — 240.0±16.3 mg) was studied to assess compliance with verapamil therapy. In ramipril trial (n=30) its mean daily dose was 8.9±0.7 mg. The following main ABPM variables were analyzed: ABPM means and variability, maximal and minimal values, nocturnal BP fall, parameters of Fourier transformation and smoothness index. The morning and evening BP means and morning BP surge (morning – evening BP) were assessed by HBPM. Student’s t-value and Mahalanobis distance were used to evaluate individual value of each variable (“morning” vs “evening” effect). This analysis was first done separately for each trial. After that, combined data were analyzed. Results. Overall antihypertensive effect was more intense with morning ramipril (p<0.05) intake and evening verapamil intake. The t-values ranged 2.2-2.3 for nocturnal BP fall; 2.0-2.1 for night-time BP variability; 3.8-4.3 for morning BP surge. The t-values of office and 24-hour BP were low (0.2-1.7). Conclusion. Morning BP surge based on HBPM is a good instrument for chronotherapy effect assessment. Evening administration of antihypertensive drugs causes nocturnal BP fall shift towards “dipper” status.

Opposite Effect of Diabetes Mellitus Induced by Streptozotocin on Oral and Intravenous Pharmacokinetics of Verapamil in Rats

The aim of this study was to report the effect of diabetes mellitus on the pharmacokinetics of verapamil in a route-dependent manner. Diabetes in rats was induced by streptozotocin. Plasma concentrations of verapamil and its metabolite, norverapamil, were measured after oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein levels of CYP3A1 and CYP3A2 in liver and intestine were measured by Western blot. It was found that diabetes significantly increased the plasma concentration of verapamil and norverapamil after oral administration, which resulted in a 74% increase in the area under the concentration-time curve (AUC) of verapamil, but the ratio of AUC((norverapamil))/AUC((verapamil)) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% after intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with that in control rats. The absolute bioavailability of verapamil was higher than that of control rats. An in vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by an increase and decrease in the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue-specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behaviors of verapamil after oral and intravenous administration to diabetic rats.

Effect of Huang-Lian-Jie-Du-Decoction on pharmacokinetics of verapamil in rats

The aim was to investigate the effect of Huang-Lian-Jie-Du-Decoction (HLJDD) on the pharmacokinetic behaviour of verapamil in rats. Rats orally received 3.33 g/kg of HLJDD extract for 14 days, and pharmacokinetics of verapamil was investigated after oral and intravenous verapamil. Norverapamil formation for assessing cytochrome P450 3A activity in hepatic and intestinal microsomes of the HLJDD-treated rats was investigated. The inhibitory effect of berberine on the formation of norverapamil in intestinal and hepatic microsomes was also evaluated. HLJDD treatment increased the plasma concentration of verapamil and decreased the plasma concentration of norverapamil, resulting in a 24% increase in the AUC(0-480) of verapamil and a 25% reduction in the AUC(0-480) of norverapamil after oral administration. However, HLJDD did not alter the pharmacokinetic behaviour of verapamil after intravenous administration. Norverapamil formation showed biphasic kinetics in both intestinal and hepatic microsomes. HLJDD treatment significantly decreased the intrinsic clearance of verapamil in intestinal microsomes, but had no effect on the hepatic metabolism of verapamil. Berberine also inhibited norverapamil formation in both intestinal and hepatic microsomes; the extent of inhibition was larger in intestinal microsomes. HLJDD displayed a route-dependent effect on the pharmacokinetics of verapamil in rats. HLJDD treatment increased the bioavailability of verapamil partly via inhibiting first-pass verapamil metabolism in the intestine.

The effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits

We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg(-1)) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg(-1)). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the C(max) and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg(-1) quercetin. There was no significant change in T(max) and terminal plasma half-life (t(1/2)) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P < 0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.

Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin

This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, norverapamil, in rats. The pharmacokinetic parameters of verapamil and norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5-64.8%, and the peak plasma concentration (C(max)) of verapamil by 34.1-65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (T(max)) and the terminal half-life (t(1/2)) of verapamil in the presence of lovastatin. The AUC and C(max) of norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.