ABSTRACT
Carboxylesterase enzymes convert a prodrug ramipril into the biologically active metabolite ramiprilat. It is prescribed for controlling ocular hypertension after oral administration. High concentrations of carboxylesterase enzymes in rectal and colon tissue can transform ramipril significantly to ramiprilat. Sustained rectal delivery of ramipril has been developed for intra-ocular pressure lowering effect using a normotensive rabbit model. Rectal suppositories have been formulated using a matrix base of HPMC K100-PEG 400-PEG 6000, incorporating varying amounts of Gelucire by the fusion moulding method. The presence of Gelucire in the suppository exhibited sustained structural relaxation-based release kinetics of RM compared to its absence. Intravenous and oral administration of ramipril has decreased IOP in the treated rabbit up to 90 and 360 min, respectively. Treated rabbits with suppositories have revealed decreased IOP for an extended period compared to the above. Formulation containing GEL 3% reduced intra-ocular pressure to 540 min, with the highest area under the decreased IOP curve. Compared to oral, the pharmacodynamic bioavailability of ramipril has been improved significantly using a sustained-release rectal suppository. A rectal suppository for sustained delivery of ramipril could be used to lower IOP significantly.
Subject(s)
Administration, Rectal , Delayed-Action Preparations , Intraocular Pressure , Prodrugs , Ramipril , Animals , Rabbits , Intraocular Pressure/drug effects , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Ramipril/administration & dosage , Ramipril/pharmacokinetics , Ramipril/pharmacology , Suppositories , Male , Biological Availability , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/pharmacology , Lipids/chemistry , Drug Liberation , Administration, Oral , Polyethylene GlycolsABSTRACT
BACKGROUND: Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking. METHODS: Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests. RESULTS: Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences. CONCLUSIONS: Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.
Subject(s)
Amlodipine/pharmacokinetics , Antihypertensive Agents/pharmacokinetics , Hypertension/drug therapy , Ramipril/pharmacokinetics , Serotonin and Noradrenaline Reuptake Inhibitors/pharmacokinetics , Venlafaxine Hydrochloride/pharmacokinetics , Amlodipine/administration & dosage , Amlodipine/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Cytochrome P-450 CYP2D6 Inhibitors/administration & dosage , Cytochrome P-450 CYP2D6 Inhibitors/adverse effects , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Databases, Factual , Drug Interactions/physiology , Drug Prescriptions/standards , Female , Humans , Hypertension/blood , Hypertension/diagnosis , Male , Ramipril/administration & dosage , Ramipril/adverse effects , Serotonin and Noradrenaline Reuptake Inhibitors/administration & dosage , Serotonin and Noradrenaline Reuptake Inhibitors/adverse effects , Venlafaxine Hydrochloride/administration & dosage , Venlafaxine Hydrochloride/adverse effectsABSTRACT
BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.
Subject(s)
Antihypertensive Agents/blood , Antihypertensive Agents/cerebrospinal fluid , Hydrochlorothiazide/blood , Hydrochlorothiazide/cerebrospinal fluid , Ramipril/blood , Ramipril/cerebrospinal fluid , Aged , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacokinetics , Blood-Brain Barrier/metabolism , Female , Humans , Hydrochlorothiazide/adverse effects , Hydrochlorothiazide/pharmacokinetics , Male , Middle Aged , Ramipril/adverse effects , Ramipril/pharmacokineticsABSTRACT
BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiotonic Agents/therapeutic use , Cardiovascular Diseases/blood , Kidney Failure, Chronic/blood , Renal Dialysis/methods , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors/blood , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Cardiotonic Agents/blood , Cardiotonic Agents/pharmacokinetics , Cardiovascular Diseases/complications , Cardiovascular Diseases/mortality , Cardiovascular Diseases/therapy , Enalapril/blood , Enalapril/pharmacokinetics , Enalapril/therapeutic use , Female , Fosinopril/blood , Fosinopril/pharmacokinetics , Fosinopril/therapeutic use , Hemorheology , Humans , Kidney Failure, Chronic/complications , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/therapy , Kidneys, Artificial , Lisinopril/blood , Lisinopril/pharmacokinetics , Lisinopril/therapeutic use , Male , Middle Aged , Perindopril/blood , Perindopril/pharmacokinetics , Perindopril/therapeutic use , Ramipril/blood , Ramipril/pharmacokinetics , Ramipril/therapeutic use , Renal Dialysis/instrumentation , Retrospective Studies , Survival AnalysisABSTRACT
In patients with chronic heart failure (CHF), the use of angiotensin-converting enzyme inhibitors, including ramipril, is recommended to reduce the risk of heart failure worsening, hospitalisation, and death. Our aim was to investigate the influence of body composition on the pharmacokinetics of ramipril and its active metabolite ramiprilat and to evaluate the changes in pharmacokinetics after prolonged therapy. Twenty-three patients with CHF who were on regular therapy with ramipril participated at the first study visit ( median age 77 years, 65 % male, and 70 % New York Heart Association Class II); 19 patients attended the second study visit and the median time between the two visits was 8 months. Pharmacokinetics were assessed using a nonlinear mixed-effects parent-metabolite model comprising two compartments for ramipril and one compartment for ramiprilat. The influence of body size and composition was best described by an allometric relationship with fat-free mass. In addition, ramipril clearance was related to patient age and daily ramipril dose, while clearance of ramiprilat was influenced by glome rular filtration rate and daily ramipril dose. There were no clinically relevant changes in the pharmacokinetics of ramipril and ramiprilat between the study visits. Due to the relatively stable pharmacokinetics of ramipril, regular outpatient visits at 6-month intervals seem appropriate to evaluate ramipril therapy.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Heart Failure , Ramipril , Humans , Ramipril/pharmacokinetics , Ramipril/administration & dosage , Ramipril/analogs & derivatives , Heart Failure/drug therapy , Male , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Aged , Female , Longitudinal Studies , Chronic Disease , Aged, 80 and over , Middle Aged , Body CompositionABSTRACT
Ramipril is an angiotensin-converting enzyme inhibitor used for hypertension and heart failure management. To date, scarce literature is available on pharmacogenetic associations affecting ramipril. The goal of this study was to investigate the effect of 120 genetic variants in 34 pharmacogenes (i.e., genes encoding for enzymes like CYPs or UGTs and transporters like ABC or SLC) on ramipril pharmacokinetic variability and adverse drug reaction (ADR) incidence. Twenty-nine healthy volunteers who had participated in a single-dose bioequivalence clinical trial of two formulations of ramipril were recruited. A univariate and multivariate analysis searching for associations between genetic variants and ramipril pharmacokinetics was performed. SLCO1B1 and ABCG2 genotype-informed phenotypes strongly predicted ramipril exposure. Volunteers with the SLCO1B1 decreased function (DF) phenotype presented around 1.7-fold higher dose/weight-corrected area under the curve (AUC/DW) than volunteers with the normal function (NF) phenotype (univariate p-value [puv] < 0.001, multivariate p-value [pmv] < 0.001, ß = 0.533, R2 = 0.648). Similarly, volunteers with ABCG2 DF + poor function (PF) phenotypes presented around 1.6-fold higher AUC/DW than those with the NF phenotype (puv = 0.011, pmv < 0.001, ß = 0.259, R2 = 0.648). Our results suggest that SLCO1B1 and ABCG2 are important transporters to ramipril pharmacokinetics, and their genetic variation strongly alters its pharmacokinetics. Further studies are required to confirm these associations and their clinical relevance.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2 , Angiotensin-Converting Enzyme Inhibitors , Genotype , Liver-Specific Organic Anion Transporter 1 , Neoplasm Proteins , Phenotype , Ramipril , Humans , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Ramipril/pharmacokinetics , Ramipril/administration & dosage , Liver-Specific Organic Anion Transporter 1/genetics , Male , Adult , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Young Adult , Female , Healthy Volunteers , Area Under Curve , Pharmacogenomic Variants , PharmacogeneticsABSTRACT
Ramipril - a drug with a large evidence base. Various aspects of choosing a drug in cardiology from the standpoint of evidence-based medicine are risen from his example.
Subject(s)
Cardiovascular Diseases/prevention & control , Ramipril , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Clinical Trials as Topic , Evidence-Based Medicine , Humans , Outcome and Process Assessment, Health Care , Ramipril/pharmacokinetics , Ramipril/therapeutic use , Therapeutic EquivalencyABSTRACT
In this paper, we present a validated UPLC-MS/MS assay for determination of ramipril and ramiprilat from human plasma samples. The assay is capable of isolating phase II metabolites (acylglucornides) of ramipril from in vivo study samples which is otherwise not possible using conventional HPLC conditions. Both analytes were extracted from human plasma using solid-phase extraction technique. Chromatographic separation of analytes and their respective internal standards was carried out using an Acquity UPLC BEH C(18) (2.1 × 100 mm), 1.7 µm column followed by mass spectrometric detection using an Waters Quattro Premier XE. The method was validated over the range 0.35-70.0 ng/mL for ramipril and 1.0-40.0 ng/mL for ramiprilat.
Subject(s)
Chromatography, High Pressure Liquid/methods , Ramipril/analogs & derivatives , Ramipril/pharmacokinetics , Tandem Mass Spectrometry/methods , Glucuronides , Humans , Ramipril/blood , Reproducibility of Results , Sensitivity and Specificity , Solid Phase Extraction , Spectrometry, Mass, Electrospray Ionization , Therapeutic EquivalencyABSTRACT
A rapid, simple, sensitive and specific LC-MS/MS method has been developed and validated for the simultaneous estimation of atorvastatin (ATO), amlodipine (AML), ramipril (RAM) and benazepril (BEN) using nevirapine as an internal standard (IS). The API-4000 LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Analytes and IS were extracted from plasma by simple liquid-liquid extraction technique using ethyl acetate. The reconstituted samples were chromatographed on C(18) column by pumping 0.1% formic acid-acetonitrile (15:85, v/v) at a flow rate of 1 mL/min. A detailed validation of the method was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 0.26-210 ng/mL for ATO; 0.05-20.5 ng/mL for AML; 0.25-208 ng/mL for RAM and 0.74-607 ng/mL for BEN with mean correlation coefficient of ≥0.99 for each analyte. The intra-day and inter-day precision and accuracy results were well with in the acceptable limits. A run time of 2.5 min for each sample made it possible to analyze more than 400 human plasma samples per day. The developed assay method was successfully applied to a pharmacokinetic study in human male volunteers.
Subject(s)
Amlodipine/blood , Benzazepines/blood , Heptanoic Acids/blood , Pyrroles/blood , Ramipril/blood , Tandem Mass Spectrometry/methods , Amlodipine/pharmacokinetics , Anticholesteremic Agents/blood , Anticholesteremic Agents/pharmacokinetics , Antihypertensive Agents/blood , Antihypertensive Agents/pharmacokinetics , Atorvastatin , Benzazepines/pharmacokinetics , Chromatography, Liquid , Drug Stability , Heptanoic Acids/pharmacokinetics , Humans , Least-Squares Analysis , Male , Nevirapine/analysis , Pyrroles/pharmacokinetics , Ramipril/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Spectrometry, Mass, Electrospray IonizationABSTRACT
OBJECTIVE: To determine the bioequivalence of 10 mg dose of ramipril tablets between the test product (Ramtace 10 mg, Unison Laboratories, Thailand) and the reference product (Tritace 10 mg, Aventis Pharma SPA, Italy). MATERIAL AND METHOD: The present study was carried out with a single dose, 2-treatment, 2-period, 2-sequence randomized crossover design under fasting condition with a minimum of 14 days washout period in 24 healthy Thai male and female volunteers. Plasma samples for determination of ramipril and ramiprilat were obtained pre-dose and at frequent intervals for up to 72 h post dose. Ramipril and ramiprilat plasma concentrations were quantified by a validated method employing high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). All ofthe pharmacokinetic parameters were investigated using non-compartmental analysis. RESULTS: The result demonstrated the 90% confidence interval (90%CI) of the geometric mean ratio (test/reference) of C max, AUC(0-72) and AUC(0-infinity) of ramipril were 97.26% (84.50%-111.93%), 100.70% (89.47%-113.34%) and 100.29% (88.90% 113.15%), respectively. For ramiprilat, the 90% CI for C max, AUC(0-72), and AUC(0-infinity) were 108.87% (103.00%-115.07%), 104.93% (100.50%-109.55%) and 103.30% (98.03%-108.85%), respectively. CONCLUSION: the 90% confidence intervals for log-transformed geometric mean test/reference formulation ratios of primary parameters were entirely within 80.00%-125.00%. Thus, it can be concluded that the test formulation was bioequivalent to the reference formulation.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Ramipril/administration & dosage , Ramipril/pharmacokinetics , Administration, Oral , Adolescent , Adult , Angiotensin-Converting Enzyme Inhibitors/blood , Asian People , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Cross-Over Studies , Female , Humans , Male , Middle Aged , Ramipril/blood , Reference Values , Tablets , Tandem Mass Spectrometry , Thailand , Therapeutic Equivalency , Young AdultABSTRACT
This open-label, repeat-dose, fixed-sequence study in healthy subjects examined pharmacokinetic drug-drug interactions between the components of a novel fixed-dose combination product containing ramipril, amlodipine, and atorvastatin. Sequential 5-day monotreatments (MTs) of ramipril (5 mg/d) and atorvastatin (40 mg/d) were followed by a 9-day amlodipine MT (5 mg/d), separated by 96 hours washout intervals. After amlodipine MT, all 3 single-entity drugs were coadministered for 5 days. Blood samples were taken over the dosing intervals and drug concentrations quantified by high-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were assessed and compared between the MTs and combination treatments by analysis of variance. Eighteen healthy subjects were enrolled and completed the study. No significant difference in maximum concentration (Cmax ) and area under the plasma concentration-time curve over the dosing interval (AUC0-τ ) for amlodipine and AUC0-τ of atorvastatin was observed upon combination treatments versus MTs. Cmax of atorvastatin was slightly decreased (Cmax ratio, 89.3%) when given in combination. Increased exposure of ramipril and less pronounced exposure of ramiprilat were observed in the presence of amlodipine and atorvastatin, with Cmax ratios for ramipril and ramiprilat of 182.6% and 155.9%, and corresponding AUC0-τ ratios of 150.0% and 112.1%, respectively. These ramiprilat increases are unlikely of clinical relevance, because complete angiotensin-converting enzyme occupation is achieved with ≥5-mg ramipril doses, and free ramiprilat is rapidly eliminated. As ramipril is known to be subject to a site-dependent absorption in the upper small intestine, it is hypothesized that slowing of intestinal motility by atorvastatin or amlodipine or a combined effect of both, increased the residence time of ramipril in its "absorption window," thereby enhancing its bioavailability.
Subject(s)
Amlodipine/pharmacokinetics , Anticholesteremic Agents/pharmacokinetics , Antihypertensive Agents/pharmacokinetics , Atorvastatin/pharmacokinetics , Drug Interactions , Gastrointestinal Motility/drug effects , Intestinal Absorption/drug effects , Ramipril/pharmacokinetics , Adult , Amlodipine/pharmacology , Anticholesteremic Agents/pharmacology , Antihypertensive Agents/pharmacology , Atorvastatin/pharmacology , Biological Availability , Drug Combinations , Healthy Volunteers , Humans , Male , Young AdultABSTRACT
BACKGROUND: The Polycap (polypill; aspirin [acetylsalicylic acid], ramipril, simvastatin, atenolol, and hydrochlorothiazide) was found to be safe and effective for reducing multiple cardiovascular risk factors in The Indian Polycap Study (TIPS). OBJECTIVE: We evaluated the bioavailability of each ingredient of the Polycap and determined any drug-drug interactions relative to single component reference preparations. METHODS: The bioavailability of the ingredients of the Polycap (T; test) when formulated as a single capsule was compared with that of identical capsules with each of its ingredients administered separately (R; reference) in a five-arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least a 2-week washout period in a total of 195 healthy volunteers. Plasma concentrations of each drug and, where applicable, its active metabolite were measured using validated liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte. RESULTS: Comparative bioavailability was computed and no drug-drug interactions and no difference in comparative bioavailability were concluded for each ingredient based on point estimates of the T/R ratio of the geometric means falling within 80-125% for peak plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC(t)), and AUC from time zero to infinity (AUC(infinity)). The T/R ratio for C(max), AUC(t) and AUC(infinity) was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose-normalized salicylic acid. However, for simvastatin, the T/R point estimates for C(max), AUC(t) and AUC(infinity) for Ln-transformed data were significantly lower ( approximately 3-4%) than the lower bound of 80%. For its active metabolite, simvastatin acid, these estimates were significantly higher ( approximately 25-35%) than the higher bound of 125%. Thus, the increased bioavailability of active simvastatin acid appeared to compensate for the loss of bioavailability of simvastatin. CONCLUSION: The Polycap was found to be effective and safe in the previously published TIPS trial. The present study in healthy volunteers establishes that Polycap is safe (no serious adverse events) and well tolerated, and that there is no indication of pharmacokinetic drug-drug interactions for any of the ingredients, with their bioavailabilities being well preserved.
Subject(s)
Antihypertensive Agents/pharmacokinetics , Hypolipidemic Agents/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacokinetics , Administration, Oral , Adolescent , Adult , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Area Under Curve , Aspirin/administration & dosage , Aspirin/adverse effects , Aspirin/pharmacokinetics , Atenolol/administration & dosage , Atenolol/adverse effects , Atenolol/pharmacokinetics , Biological Availability , Capsules , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Chromatography, Liquid/methods , Cross-Over Studies , Drug Combinations , Drug Interactions , Humans , Hydrochlorothiazide/administration & dosage , Hydrochlorothiazide/adverse effects , Hydrochlorothiazide/pharmacokinetics , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/adverse effects , Male , Middle Aged , Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/adverse effects , Ramipril/administration & dosage , Ramipril/adverse effects , Ramipril/pharmacokinetics , Risk Factors , Simvastatin/administration & dosage , Simvastatin/adverse effects , Simvastatin/pharmacokinetics , Tandem Mass Spectrometry/methods , Young AdultABSTRACT
We conducted 3 open-label, multiple-dose, 3-period, randomized, crossover studies in healthy subjects to assess the potential pharmacokinetic interaction between vildagliptin, a novel dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, and representatives of 3 commonly prescribed antihypertensive drug classes: (1) the calcium channel blocker, amlodipine; (2) the angiotensin receptor blocker, valsartan; and (3) the angiotensin-converting enzyme inhibitor, ramipril. Coadministration of vildagliptin 100 mg with amlodipine 5 mg, valsartan 320 mg, or ramipril 5 mg had no clinically significant effect on the pharmacokinetics of these drugs. The 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24h) and maximum plasma concentration (Cmax) for vildagliptin, amlodipine, and ramipril (and its active metabolite, ramiprilat) were contained within the acceptance range for bioequivalence (0.80-1.25). Valsartan AUC0-24h and Cmax increased by 24% and 14%, respectively, following coadministration of vildagliptin, but this was not considered clinically significant. Vildagliptin was generally well tolerated when given alone or in combination with amlodipine, valsartan, or ramipril in healthy subjects at steady state. No adjustment in dosage based on pharmacokinetic considerations is required should vildagliptin be coadministered with amlodipine, valsartan, or ramipril in patients with type 2 diabetes and hypertension.
Subject(s)
Adamantane/analogs & derivatives , Amlodipine/pharmacokinetics , Antihypertensive Agents/pharmacokinetics , Dipeptidyl-Peptidase IV Inhibitors/pharmacokinetics , Nitriles/pharmacokinetics , Pyrrolidines/pharmacokinetics , Ramipril/analogs & derivatives , Tetrazoles/pharmacokinetics , Valine/analogs & derivatives , Adamantane/administration & dosage , Adamantane/adverse effects , Adamantane/pharmacokinetics , Administration, Oral , Adult , Amlodipine/administration & dosage , Amlodipine/adverse effects , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin II Type 1 Receptor Blockers/adverse effects , Angiotensin II Type 1 Receptor Blockers/pharmacokinetics , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Area Under Curve , Cross-Over Studies , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Drug Interactions , Female , Half-Life , Headache/chemically induced , Humans , Male , Middle Aged , Nausea/chemically induced , Nitriles/administration & dosage , Nitriles/adverse effects , Pyrrolidines/administration & dosage , Pyrrolidines/adverse effects , Ramipril/administration & dosage , Ramipril/adverse effects , Ramipril/pharmacokinetics , Tablets , Tetrazoles/administration & dosage , Tetrazoles/adverse effects , Valine/administration & dosage , Valine/adverse effects , Valine/pharmacokinetics , Valsartan , VildagliptinABSTRACT
The pharmacokinetics of ramipril and its active metabolite, ramiprilat, was determined in cats following single and repeated oral doses of ramipril (Vasotop tablets) (once daily for 9 days) at dose rates of 0.125, 0.25, 0.5 and 1.0 mg/kg. The pharmacodynamic effects were assessed by measuring plasma angiotensin-converting enzyme (ACE) activity. Maximum ramipril concentrations were attained within 30 min following a single dose and declined rapidly (concentrations were below the limit of quantification 4 h after treatment). Peak ramiprilat concentrations were detected at approximately 1.5 h. The apparent terminal half-life (t((1/2)beta)) was > or =20 h irrespective of the dose. Ramiprilat accumulated in plasma (ratio of accumulation 1.3 to 1.9 depending on the dose rate) following repeated administration. Steady-state conditions were attained after the second dose. Excretion was predominant in faeces (87%) and to a lesser extent in urine (11%). The rate and extent of absorption of ramipril as well as its conversion to ramiprilat were not significantly influenced by the presence of food in the gastrointestinal tract. Plasma-ACE activity was almost completely abolished 0.5-2.0 h after treatment, irrespective of the dose rate. Significant inhibition of ACE activity of 54.7 to 82.6% (depending on the dosage) was still present 24 h after treatment. Treatment was well-tolerated in all cats. Ramipril at a dose rate of 0.125 mg/kg once daily produces significant and long-lasting inhibition of ACE activity in healthy cats. The appropriateness of this dosage regime needs to be confirmed in diseased cats.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Peptidyl-Dipeptidase A/drug effects , Ramipril/analogs & derivatives , Ramipril/pharmacokinetics , Administration, Oral , Angiotensin-Converting Enzyme Inhibitors/blood , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Area Under Curve , Cats , Dose-Response Relationship, Drug , Female , Half-Life , Male , Metabolic Clearance Rate , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/metabolism , Ramipril/blood , Ramipril/pharmacology , Reference ValuesABSTRACT
An isotope dilution selective and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) method has been developed for the simultaneous determination of hydrochlorothiazide (HCTZ) and ramipril in human plasma through a new concept of periodical polarity switching. Extraction of HCTZ, ramipril and their deuterated analogs as internal standards (ISs) was carried out from 150 µL of human plasma by solid-phase extraction method. Chromatographic separation of analytes was performed on Hypurity C18 (150 mm × 4.6 mm, 5 µ) column under gradient conditions with methanol:0.2% (v/v) formic acid in water as the mobile phase. The method was validated over a concentration range of 0.750-300 ng/mL for HCTZ and 0.125-80.0 ng/mL for ramipril. The mean extraction recovery for analytes and ISs were >(86.0%), consistent across all four QC levels. The challenges to evaluate matrix effect and continuous reproducibility of method during long analytical run was studied and resolved. Processed samples, freeze-thaw, long-term and whole blood stability were evaluated for both the analytes. The method was applied to support a bioequivalence study of 25 mg of HCTZ and 5 mg of ramipril tablet formulation in nine healthy Indian subjects. Assay reproducibility was demonstrated by reanalysis of 42 incurred samples.
Subject(s)
Chromatography, Liquid/methods , Hydrochlorothiazide/blood , Ramipril/blood , Tandem Mass Spectrometry/methods , Humans , Hydrochlorothiazide/pharmacokinetics , Limit of Detection , Linear Models , Ramipril/pharmacokinetics , Reproducibility of Results , Solid Phase Extraction , Spectrometry, Mass, Electrospray Ionization , Tablets , Therapeutic EquivalencyABSTRACT
The objective of our investigation was to design a thermodynamically stable and dilutable nanoemulsion formulation of Ramipril, with minimum surfactant concentration that could improve its solubility, stability and oral bioavailability. Formulations were taken from the o/w nanoemulsion region of phase diagrams, which were subjected to thermodynamic stability and dispersibility tests. The composition of optimized formulation was Sefsol 218 (20% w/w), Tween 80 (18% w/w), Carbitol (18% w/w) and standard buffer solution pH 5 (44% w/w) as oil, surfactant, cosurfactant and aqueous phase, respectively, containing 5 mg of ramipril showing drug release (95%), droplet size (80.9 nm), polydispersity (0.271), viscosity (10.68 cP), and infinite dilution capability. In vitro drug release of the nanoemulsion formulations was highly significant (p<0.01) as compared to marketed capsule formulation and drug suspension. The relative bioavailability of ramipril nanoemulsion to that of conventional capsule form was found to be 229.62% whereas to that of drug suspension was 539.49%. The present study revealed that ramipril nanoemulsion could be used as a liquid formulation for pediatric and geriatric patients and can be formulated as self-nanoemulsifying drug delivery system (SNEDDS) as a unit dosage form.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemistry , Emulsions , Nanoparticles , Oils/chemistry , Ramipril/chemistry , Administration, Oral , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/blood , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Animals , Biological Availability , Buffers , Capsules , Chemistry, Pharmaceutical , Drug Compounding , Drug Stability , Ethylene Glycols/chemistry , Hydrogen-Ion Concentration , Male , Models, Biological , Pharmaceutical Solutions , Phase Transition , Polysorbates/chemistry , Ramipril/administration & dosage , Ramipril/blood , Ramipril/pharmacokinetics , Rats , Rats, Wistar , Solubility , Surface-Active Agents/chemistry , Technology, Pharmaceutical/methods , Thermodynamics , ViscosityABSTRACT
Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged > or =55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiovascular Diseases/prevention & control , Ramipril/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Female , Humans , Male , Middle Aged , Ramipril/adverse effects , Ramipril/pharmacokineticsABSTRACT
BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4 degrees C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Models, Biological , Ramipril/analogs & derivatives , Administration, Oral , Adult , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Binding Sites , Biological Availability , Humans , Injections, Intravenous , Male , Peptidyl-Dipeptidase A/blood , Ramipril/administration & dosage , Ramipril/pharmacokinetics , Randomized Controlled Trials as Topic , Reproducibility of Results , Substrate SpecificityABSTRACT
OBJECTIVE: To assess the bioequivalence of a ramipril 5 mg tablet formulation (ramipril test formulation from Laboratórios Biosintética Ltda (Sao Paulo, Brazil) and Triatec from Aventis Pharma (Sueano, Brazil) standard reference formulation) in 26 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, 2-period crossover design with a 2-week washout interval. Plasma samples were obtained over a 36-hour period. Plasma ramipril and ramiprilat concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the ramipril and ramiprilat plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained: AUClast, AUCinf and Cmax. RESULTS: The limit of quantification was 0.2 ng x ml(-1) and 1.0 ng x ml(-1) for ramipril and ramiprilat, respectively. The geometric means and 90% confidence intervals (CI) for Ramipril/Triatec and Ramiprilat/Triatec percent ratios were: 104.69% (90% CI = 93.21-117.59%) for Cmax, 102.49% (90% CI = 92.76-113.24%) for AUClast, 103.60% (90% CI = 93.56 114.73%) for AUCinf, 108.48% (90% CI = 98.86-119.03%) for Cmax, 105.88% (90% CI = 101.55-110.39%) for AUClast, 97.30% (90% CI = 90.17-104.99%) for AUCinf, respectively. CONCLUSION: Since the 90% CI for AUClast, AUCinf and Cmax ratios were within the 80-125% interval proposed by the U.S. FDA, it was concluded that the ramipril formulation produced by Laboratórios Biosintética Ltda is bioequivalent to the Triatec formulation in both rate and extent of absorption.
Subject(s)
Antihypertensive Agents/pharmacokinetics , Ramipril/pharmacokinetics , Administration, Oral , Adolescent , Adult , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/blood , Area Under Curve , Biological Availability , Chemistry, Pharmaceutical/methods , Chromatography, Liquid/methods , Cross-Over Studies , Female , Humans , Male , Mass Spectrometry/methods , Middle Aged , Ramipril/administration & dosage , Ramipril/analogs & derivatives , Ramipril/blood , Reference Values , Spectrometry, Mass, Electrospray Ionization/methods , Therapeutic Equivalency , Time FactorsABSTRACT
This study presents a rapid, specific and sensitive LC-MS/MS assay for the determination of ramipril and ramiprilat in human serum using enalapril as an internal standard (IS). A Waters Atlantis C18 column (2.1 mm x 100 mm, 3 microm) and a mobile phase consisting of 0.1% formic acid-methanol (25:75, v/v) were used for separation. The analysis was performed by the selected reaction monitoring (SRM) method, and the peak areas of the m/z 417.3-->234.3 and m/z 389.3-->206.2 transition for ramipril and ramiprilat, respectively, were measured versus that of the m/z 377.3-->234.2 for IS to generate the standard curves. The assay linearities of ramipril and ramiprilat were confirmed over the range 0.10-100 ngml(-1) and 0.25-100 ngml(-1), respectively, and limits of quantitation for them were 0.10 and 0.25 ngml(-1), respectively. The linear ranges correspond well with the serum concentrations of the analytes obtained in clinical pharmacokinetic studies. Intraday and interday relative standard deviations of ramipril and ramiprilat were 2.8-6.4% and 4.3-4.6%, 4.4-6.7% and 3.5-4.7%, respectively. The recoveries of ramipril and ramiprilat from serum were in the range of 81.0-98.2%. The developed LC-MS procedures were applied for the determination of the pharmacokinetic parameters of ramipril and ramiprilat following a single oral administration of 10mg ramipril tablets in 18 Chinese healthy male volunteers.