Pharmacokinetics of two enteric-coated ketoprofen products in humans with or without coadministration of omeprazole and comparison with dissolution findings.
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Adolescent↗
Biomedical subjects
G Caillé
Publications and source records attributed to G Caillé.
Influence of drug formulation on drug concentration-effect relationships.
Slow release formulations (SRFs) are developed on the basis that the response elicited by a drug is closely related to changes in its plasma concentrations. As a consequence, the drug in the SRF is considered bioequivalent to the same drug administered in a conventional or immediate release formulation (IRF). The available literature suggest that for drugs eliciting a simple response, i.e. theophylline, the response is not affected by the rate of input of drug into the systemic circulation. Therefore, the pharmacodynamics are closely related to the pharmacokinetics of the drug, which are independent of formulation. In this case, SRFs and IRFs are truly bioequivalent. The pharmacological effect of some drugs, e.g. nifedipine, prazosin, furosemide (frusemide), etc., triggers compensatory homeostatic mechanisms. Therefore, the measured effect may not directly relate to the plasma drug concentration. Furthermore, the characteristics of the response will be modulated by the rate of input of the drug, i.e. drugs in SRF will elicit a greater response because a slow input triggers fewer homeostatic reactions. As a consequence, for drugs that trigger homeostatic reactions, a drug released from an SRF may not be bioequivalent to the same drug released from an IRF. Finally, when tolerance to an effect develops, a drug administered as an SRF will elicit a smaller effect than when administered as an IRF. Therefore, even if the different formulations of a drug were bioequivalent on the basis of pharmacokinetic parameters, they would not be equivalent on the basis of pharmacodynamic factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Absorption↗
Clentiazem given at reperfusion improves subendocardial reflow and reduces myocardial infarct size in the dog.
The postischemic cardioprotection by calcium antagonists and the interplay between neutrophils and regional myocardial blood flow were investigated further, using clentiazem, a new potent calcium channel blocker derived from diltiazem. A 90-min occlusion of the interventricular coronary artery was followed by 6 hr of reperfusion in anesthetized dogs. One group was given clentiazem: 100 micrograms/kg at 5 min before reperfusion followed by a perfusion of 1 microgram/kg/min until sacrifice; controls received saline. Infarct size (% of area at risk) estimated with triphenyltetrazolium staining and by histology was reduced by nearly 50% (P < .05) in treated (16.6 +/- 3.0%), as compared to control (31.6 +/- 6.3%) dogs. Regional and collateral myocardial flows estimated with radioactive microspheres were similar between groups before and during occlusion. However, after an initial recovery to preocclusion values at 30-min reperfusion in both groups, flow declined to 50% normal (P < .05) in control animals after 3 and 6 hr in midwall and subendocardium, but the change was remarkably attenuated (P < .05) in subendocardium of clentiazem-treated dogs. Also, neutrophil accumulation at the epicardial side of the infarct, at the edge of salvaged myocardium, and estimated by tissue myeloperoxidase measurement, was reduced by 50% in treated dogs (clentiazem: 17.2 +/- 2.8; controls: 32.3 +/- 2.7 x 10(6) neutrophils/g). We conclude that administration of clentiazem at reperfusion reduces infarct size by interfering with both neutrophil accumulation and development of subendocardial no reflow in reperfused myocardium.
Animals↗
Stereospecific high-performance liquid chromatographic assay of ibuprofen: improved sensitivity and sample processing efficiency.
A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of the non-steroidal anti-inflammatory drug ibuprofen (IB) in plasma was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), samples are acidified and extracted with a mixture of isooctane-isopropanol (95:5, v/v). After evaporation of the organic layer, the drug and I.S. are derivatized with S-(-)-1(1-naphthyl)ethylamine (S-NEA) after addition of ethyl chloroformate as the coupling reagent. Ethanolamine is added 3 min after the addition of S-NEA to react with the excessive ethyl chloroformate. The resultant diastereomers corresponding to IB and I.S. were chromatographed at ambient temperature on a 100 mm x 4.6 mm I.D. C18 reversed-phase column using acetonitrile-water-acetic acid-triethylamine (60:40:0.1:0.02) as the mobile phase pumped at a flow-rate of 1.2 ml/min. Detection of the fluorescent chromophore was at 280 and 320 nm for excitation and emission, respectively. The suitability of the assay for clinical pharmacokinetic studies of IB was determined by the analysis of plasma samples obtained from a healthy volunteer, following administration of a single 400-mg oral dose of racemic IB.
Chromatography, High Pressure Liquid↗
Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method.
Twenty-four young healthy volunteers received a single dose of metformin 500 mg (Glucophage, Nordic Laboratories, Canada) in tablet form. Plasma concentrations were determined by HPLC in samples collected prior to and 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18, 24, and 30 h after dosing. Mean (+/- SD) Cmax was 682.1 (160.6) ng ml-1 at a mean (+/- SD) tmax of 2.4 (0.93) h. Overall elimination was monoexponential with a mean (+/- SD) half-life of 3.16 (0.47) h. We conclude that metformin is rapidly absorbed from this formulation and is also rapidly eliminated. Extrapolation to steady state predicts that equilibrium will be reached within 24 h.
Adult↗
Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers.
Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.
Adult↗
Pharmacodynamics as a tool to assess the bioequivalence of non-systemically available drugs: size of the sample required.
Bioequivalence studies of drugs which are not systematically available must rely on the measure of the pharmacological response. Detection of a difference between two such preparations is often hampered by the need to include an elevated number of subjects. The number of subjects can be reduced whenever: (a) the characteristics of the subjects are well defined, (b) the selection of the baseline target effect is done rigorously, (c) the target effect can be quantified reliably, (d) the effect is measured when less variability is expected, e.g. at steady state, (e) the effect is measured repeatedly, and (f) when possible, the predicted maximal effect (Emax) and the concentration to elicit 50% of Emax are estimated. A simple equation has been derived to estimate the number of subjects needed in these bioequivalence studies.
Cohort Studies↗
Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man.
The pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 x 400 mg doses of Nurofen were determined in 12 healthy volunteers. Terminal half-lives were similar for both enantiomers, but plasma levels of S-ibuprofen were higher than those of R-ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time-dependency. A large inter-individual variability in the ratio of S- to R-ibuprofen average concentrations at steady-state was observed (mean +/- SD 1.89 +/- 0.89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.
Adult↗
Effect of congestive heart failure on clentiazem pharmacokinetics in a dog model.
Clentiazem, 8-chloro diltiazem, is a calcium channel blocker currently undergoing evaluation for the treatment of stable angina and hypertension. As patients with ischaemic disorders often present some degree of heart failure, the aim of this study was to investigate the effect of congestive heart failure on clentiazem (200 micrograms kg-1, i.v. bolus) pharmacokinetics in a canine model. Congestive heart failure was induced in six dogs by rapid ventricular pacing (240 beats min-1) for 3-5 weeks. Clentiazem pharmacokinetics was studied in each dog under the control condition and after the development of clinical signs of heart failure (ascites, dyspnea, fatigue). Blood samples were collected up to 480 min post-dose. Clentiazem plasma concentrations were determined by high performance liquid chromatography. The area under the plasma concentration versus time curves (AUC0-infinity) was significantly increased in congestive heart failure dogs (8.8 +/- 1.6 vs 21.8 +/- 1.4 micrograms min ml-1) (mean +/- SEM). These changes were related to a reduction of the volume of distribution of the central compartment (0.9 +/- 0.1 vs 0.2 +/- 0.11 kg-1) and total body clearance (1.9 +/- 0.4 vs 0.7 +/- 0.21 h-1 kg-1). It is concluded that, in our model, congestive heart failure significantly modifies clentiazem disposition. These results suggest that caution should be exercised when clentiazem is given to patients with a low ejection fraction and a compromised cardiac function. Reduced loading and maintenance doses might be recommended in patients with severe congestive heart failure.
Animals↗
Effect of an acute dose of alcohol on the pharmacokinetics of oral nifedipine in humans.
Pharmacokinetic and pharmacodynamic interactions of alcohol and nifedipine were assessed in 10 healthy human volunteers. Doses of 20 mg (2 x 10-mg capsules) of nifedipine were administered with either 150 ml of orange juice or 75 ml of alcohol (94%) in 75 ml of orange juice according to a crossover randomized design. Plasma nifedipine levels were monitored for 16 hr after each dosing, along with pulse rate and blood pressure. The relative bioavailability of nifedipine, measured as AUC, was increased by 54% (533 vs 346 ng.hr/ml) after the dose of alcohol (P less than 0.0002). However, there were no significant differences between treatments in Cmax, tmax, or t1/2. Although there was no difference in the systolic and diastolic blood pressure and pulse rate between the two treatment groups, the time to reach peak heart rate was significantly faster in the group treated with alcohol (1.4 vs 2.2 hr). This study shows that ethanol increases the bioavailability of nifedipine and decreases the time for onset of increased heart rate.
Administration, Oral↗
Pharmacokinetics of oral diltiazem and five of its metabolites in patients with chronic renal failure.
The pharmacokinetics of oral diltiazem were studied in 10 patients with chronic renal failure not requiring dialysis and in five healthy volunteers after a single dose of 120 mg. We found that patients with chronic renal failure had lower amounts of unchanged diltiazem and of its main metabolite (MA) in urine and a trend to have slightly higher values of plasma concentration. Since the terminal elimination phase is not affected by chronic renal failure we conclude that this trend is probably the result of alterations in the volume of distribution of diltiazem in these patients.
Administration, Oral↗
Pharmacokinetics of intravenous diltiazem and five of its metabolites in patients with chronic renal failure and in healthy volunteers.
The pharmacokinetics of diltiazem were studied in seven patients with chronic renal failure (CRF) not requiring dialysis and in three healthy volunteers after a rapid i.v. infusion of 20 mg. Mean plasma concentrations at the end of infusion were 3.15 times higher in patients with CRF than in healthy volunteers. From 0.5 to 12 h post-infusion, the difference remained between 25 per cent and 73 per cent. Mean AUC0-infinity was statistically greater in patients than in volunteers while mean V area, CLtot, and CLren were statistically lower. The t1/2 alpha and t1/2 beta values were not significantly (p greater than 0.05) different between patients and volunteers. Renal excretion was statistically more important in volunteers (6.6 per cent of the dose) than in patients (1.2 per cent of the dose). We therefore conclude that CRF does not influence t1/2 beta of diltiazem but it interferes with the extent and possibly the rate of its extravascular distribution. That could result in transient high plasma concentrations after rapid i.v. infusion.
Adult↗
Peripheral vasodilator and cardiac properties of the 1,5-benzothiazepine calcium antagonist analog, TA-3090, in dogs.
Diltiazem, a 1,5-benzothiazepine, has demonstrated efficacy in the treatment of numerous cardiovascular diseases. TA-3090, a newly synthetized 1,5-benzothiazepine compound was studied in open-chest anesthetized dogs to characterize its hemodynamic properties, to compare it with diltiazem, and finally to correlate hemodynamic properties and plasma level concentrations. Anesthetized open-chest dogs were instrumented with electronic devices and fluid-filled catheters to monitor cardiac, coronary, and peripheral hemodynamic changes. A cumulative intravenous bolus administration of TA-3090 (n = 16) or diltiazem (n = 15) (15, 50, 200, and 400 micrograms/kg) was carried out, and blood samples were taken before and 5 min following each dose administration. Hemodynamic changes were followed for 30 min after each administration, at which time most hemodynamic parameters were back to baseline levels. The results indicate that both TA-3090 and diltiazem elicit slight peripheral and coronary vasodilator properties at low doses (15 and 50 micrograms/kg). With higher dosage, hemodynamic effects were maximal: coronary blood flow increased by 75%, arterial pressure decreased by 25%, and reflex positive inotropic effects were also observed. Heart rate was significantly reduced (10%). Comparison between TA-3090 and diltiazem indicates that both drugs elicit coronary vasodilator selectivity and TA-3090 has a prolonged duration of action compared with that of diltiazem. A straightforward relationship is demonstrated between vasodilator properties and plasma levels of either TA-3090 or diltiazem. Our data suggest that with plasma levels between 40 and 80 ng/mL, significant hemodynamic changes were observed with TA-3090. Changes of heart rate were not correlated with plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Influence of food on the bioavailability of diltiazem and two of its metabolites following the administration of conventional tablets and slow-release capsules.
The influence of food on the bioavailability of a conventional tablet and of a slow-release capsule of diltiazem was investigated in two separate groups of 24 healthy volunteers in two open crossover studies. Diltiazem, as a conventional tablet (2 x 30 mg, first group) or as a slow-release capsule (120 mg SR, second group), was administered in a fasting condition and 30 min after a breakfast of 784 kcal (23 per cent proteins, 55 per cent lipids, and 22 per cent of carbohydrates). Multiple blood samples were withdrawn during the next 24 h and diltiazem, desmethyldiltiazem, and deacetyldiltiazem were assayed by HPLC. Neither the rate of absorption, assessed by the rate constant of absorption, the peak plasma concentration, and the time required to reach the peak, nor the amount of drug reaching the systemic circulation, assessed by the area under the plasma concentration time curve (AUC infinity) were influenced by food, and that independently of the formulation. Compared to the fasting experiment, food did not affect either the rate of formation or the AUC infinity of desmethyldiltiazem or deacetyldiltiazem. The results of the present study show that the relative bioavailability of the single dose of diltiazem administered as a slow-release capsule is significantly higher (69 per cent) than that estimated after the administration of diltiazem in a conventional tablet. It was concluded that food does not influence the bioavailability of diltiazem administered as a conventional tablet or as a slow-release formulation.
Administration, Oral↗
Multiple-dose propranolol administration does not influence the single dose pharmacokinetics of quinapril and its active metabolite (quinaprilat).
To evaluate the influence of multiple dose propranolol administration on the single dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, a drug-drug interaction study was performed in ten healthy volunteers. Each subject received a single 20 mg quinapril oral dose on Days 1 and 16 of the study. Oral propranolol doses of 40 mg BID were initiated on Day 3, titrated gradually to 80 mg TID by Day 10, and continued at 80 mg TID through Day 17. Comparable mean quinapril pharmacokinetic parameter values as well as comparable mean quinaprilat pharmacokinetic parameter values determined following quinapril administered alone and following quinapril administered with propranolol, indicate that propranolol does not alter the single dose pharmacokinetics of quinapril or quinaprilat.
Adult↗
Effects of food and sucralfate on the pharmacokinetics of naproxen and ketoprofen in humans.
Compliance to nonsteroidal anti-inflammatory drug therapy can be compromised by gastrointestinal side effects. To overcome this problem, food, antacid, or sucralfate are often co-administered with nonsteroidal anti-inflammatory drugs. Three studies were conducted on three groups of 12 volunteers in order to determine the influence of food or sucralfate on the pharmacokinetics of naproxen and ketoprofen. In a crossover experimental design, the first group received a single dose (50 mg) of ketoprofen with and without sucralfate (2 g). The second group received single (100 mg) and multiple (100 mg twice daily for 5 days) doses of enteric-coated ketoprofen with and without food. The third group received single (500 mg) and multiple (500 mg twice daily) doses of naproxen with and without sucralfate. Multiple blood samples were drawn and analyzed by high-pressure liquid chromatography. Short- and long-term pharmacokinetic parameters were determined. Results in group 1 showed that neither ketoprofen bioavailability nor maximal plasma concentration and time to reach maximal concentration were affected by the administration of sucralfate. However, in group 2 absorption of ketoprofen was markedly affected by food. In the presence of food, maximal plasma concentration decreased from 10.7 to 6.3 micrograms/ml after single-dose administration and 12.1 to 8.0 micrograms/ml after multiple-dose administration. The time to reach maximal plasma concentration was also modified by food, increasing from 2.8 to 7.1 hours after single-dose and 2.8 to 7.6 hours after multiple-dose administration. Food caused a significant decrease in the bioavailability of ketoprofen (over 40 percent) following both single-dose (23.8 versus 13.1 micrograms.hour/ml) and multiple-dose (29.3 versus 16.8 micrograms.hour/ml) administration. Results obtained in group 3 showed that sucralfate reduced the absorption rate constant of naproxen, from 1.7 to 1.2 hours-1 and from 1.5 to 0.7 hour-1 following single- and multiple-dose administration, respectively. However, bioavailability of naproxen was not affected by sucralfate administration. Overall, these studies have shown that sucralfate does not alter the pharmacokinetics of naproxen and ketoprofen; the amount of drug absorbed remains constant. However, plasma concentrations of ketoprofen after single- and multiple-dose administration were greatly affected by food, with a decrease of greater than 40 percent in bioavailability.
Adolescent↗
Determination of opiates and other basic drugs by high-performance liquid chromatography with electrochemical detection.
A procedure is described for the extraction and determination of morphine (M), hydromorphone (HM), codeine (C) and metoclopramide (MCP) present in human plasma. The drugs are separated by reversed-phase liquid chromatography and detected amperometrically at a glassy carbon electrode. The method provides high sensitivity and selectivity and has been used successfully in bioavailability studies.
Biological Availability↗
Chloroform interaction with chlordecone and mirex: correlation between biochemical and histological indices of toxicity and quantitative tissue levels.
The purpose of this study was to investigate whether the tissue distribution of chlordecone (CD) and mirex (M) might explain the difference in the potentiation of CHCl3 liver injury. Male Sprague-Dawley rats received either a single oral dose of CD or M (1, 2.5, 5, 10, 25, or 50 mg/kg) or three single daily doses of CD or M (0.5, 2, or 10 mg/kg). Eighteen hours following the last treatment, the animals were divided into two groups. The first group was killed and residues of CD or M in plasma, kidney, liver, and adipose tissue were measured by gas-liquid chromatography. The other group received CHCl3 (0.5 ml/kg, po) and was killed 24 hr later. Biochemical and histological indices of liver injury were evaluated. CD administered either singly or repetitively is more effective than M in potentiating the CHCl3-induced liver injury. This was exhibited by a higher increase in the plasma activities of the enzymes alanine aminotransferase and ornithine carbamoyl transferase and a greater alteration of the morphological pattern. There was a very good correlation between biochemical and histological indices. However, the severity of the liver injury did not parallel tissue concentrations. With M, a relatively poor potentiation of the liver damage was observed although adequate hepatic concentrations were present.
Adipose Tissue↗