Relationship of changes in felodipine pharmacokinetics to haemodynamics during chronic oral treatment of congestive heart failure patients.

In congestive heart failure patients the kinetics of felodipine, a dihydropyridine calcium antagonist, show interpatient differences after acute i.v. administration that disappear after 8 weeks oral treatment with a change in kinetics in the patients with the largest clearances (CL) and the smallest volumes of distribution (Vss). Pharmacokinetic and haemodynamic data were combined to construct a haemodynamic-pharmacokinetic model. This model shows that the differences between the patients in i.v. pharmacokinetics are consistent with a difference in plasma flow distribution between liver and poorly perfused tissues. In patients in whom kinetics changed, felodipine treatment is supposed to cause a redistribution of flow from liver to peripheral tissues, accompanied by a decreased work load of the heart and a larger increase in VO2max during therapy than in the other patients, whose workload increased. This suggests a better therapeutic response in the patients whose kinetics changed. As change in kinetics is related to felodipine CL and CL to liver plasma flow, felodipine CL or even indocyanine CL might be predictive for the therapeutic effect of felodipine.

Prolonged paralysis after long-term, high-dose infusion of pancuronium in anaesthetized cats.

We have studied the neuromuscular effects of a 48-h infusion of high-dose pancuronium (400 micrograms kg-1 h-1) in four cats anaesthetized with pentobarbitone, using contraction of tibialis anterior muscles after direct and indirect stimulation. After cessation of the pancuronium infusion, prolonged paralysis existed. The first twitch in the train-of-four stimuli (TOF) reappeared 8-12 h after termination of the pancuronium infusion. Twenty-four hours after termination of the infusion, TOF ratios were less than 0.08 and twitch contraction averaged 39 (SE 8)% of initial values. Twitch contraction after direct stimulation did not differ from initial values. Antagonism of paralysis was accomplished with neostigmine 60 micrograms kg-1 in two animals and neostigmine 90 micrograms kg-1 and 4-aminopyridine 500 micrograms kg-1 in the others. Steady-state plasma concentration of pancuronium (2000 ng ml-1) decreased rapidly after termination of the infusion, but then stabilized at about 130 ng ml-1. These results indicate that prolonged paralysis after long-term administration of high-dose pancuronium is caused primarily by failure of neuromuscular transmission, most likely caused by the persistent plasma concentrations of the drug in the pharmacologically active range.

Pharmacokinetics of steroidal muscle relaxants in isolated perfused rat liver.

Both in humans and animals hepatic elimination is an important factor determining the duration of action of non-depolarizing neuromuscular blocking drugs. To elucidate the hepato-biliary disposition of muscle relaxants the pharmacokinetics of several structurally related but physicochemically distinct steroidal neuromuscular blocking drugs were studied in isolated perfused rat livers. Pharmacokinetics analysis with the DIFFIT computer program enabled the simultaneous fitting of independently measured perfusate disappearance and biliary excretion rate curves using a numerical approach. The hepatic disposition of the steroidal muscle relaxants could be adequately described by a three compartment model with elimination from the peripheral compartment V2 (biliary excretion) and storage in a deep compartment (V3) connected to V2. In addition, for vecuronium only slow ester hydrolysis occurring in V2 and V3 was included in the model. The lipophilicity rather than the relative mobility of the muscle relaxants showed a positive relationship with biliary clearance (Cl20) and the initial hepatic uptake (Cl12), indicating that hepato-biliary transport of these organic cations is highly dependent on the hydrophobic character of the compounds. In addition, net hepatic uptake of the steroidal cations was influenced markedly by transport from the liver to perfusate (hepatic efflux). This hepatic efflux (k21) decreased with increasing lipophilicity. In contrast, the extent of intracellular sequestration into deep compartments, indicated by high k23/k32 ratios, seemed to be inversely related to the lipophilicity of the muscle relaxants and might explain the observed prolonged hepatic storage of some of these compounds. In combination with data from subfractionation studies the results indicate that the pharmacokinetic analysis of the hepatic disposition of steroidal muscle relaxants may be used to evaluate actual transport phenomena participating in the hepatic disposition of these drugs.

Suramin reverses non-depolarizing neuromuscular blockade in rat diaphragm.

Unexpectedly, it was observed that the P2-purinoceptor antagonist, suramin (10 microM to 1 mM), reversed the muscle paralysis caused by structurally unrelated non-depolarizing relaxants. Suramin competitively reversed the blocking action of pancuronium. Both the pre- and postsynaptic blockade of nicotinic receptors by pancuronium was counteracted, as shown by the action of suramin, using train-of-four stimulation. Suramin did not affect the paralysis caused by the depolarizing relaxant, succinylcholine. The reversal action of suramin was not due to an increase in the acetylcholine concentration in the synaptic cleft, since neither the contraction of preparations partially paralysed by diminished acetylcholine release in the presence of low Ca2+ or high Mg2+ nor acetylcholinesterase activity were affected. Suramin did not affect the reduction in twitch tension caused by adenosine and potentiated the ATP-induced reduction in twitch, indicating that ATP-sensitive receptors are not involved in the reversal action of suramin. Consequently, these results suggest that the action of suramin is due to binding with a site on the acetylcholine receptor also occupied by non-depolarizing relaxants, but different from the site occupied by succinylcholine.

Role of partial agonism in selectivity of benzodiazepines.

In pharmacological research and education a barrier often exists between pharmacodynamics and pharmacokinetics. It is helpful to construct models in which pharmacodynamics and pharmacokinetics are linked to improve insight into the situation in vivo. Arnold Scaf presents such a model which describes the contribution of intrinsic activity to the selective anxiolytic/anticonvulsant action of fully and partially agonistic benzodiazepines. It is based on the pharmacodynamic model, presented in TiPS by Haefely et al. last year.

Pharmacokinetics of pancuronium in patients undergoing coronary artery surgery with and without low dose dopamine.

Pancuronium is frequently used in coronary artery surgery, but its pharmacokinetics in these patients are still unknown. It is possible that dopamine, administered to prevent renal impairment induced by the surgery, might promote the elimination of pancuronium. Therefore, the pharmacokinetics of a bolus dose of pancuronium were studied in 2 groups of coronary artery surgery patients, with and without dopamine 2 micrograms/kg/min, administered during and after cardiopulmonary bypass. Dopamine in the administered dose did not influence the systemic haemodynamics. The pharmacokinetic variables in both groups did not differ from those found in an earlier study in healthy normothermic patients. Total renal clearance was not influenced by dopamine, due to post-bypass rebound hyperperfusion in the control group. Pancuronium was shown to be subject to considerable tubular reabsorption, and its elimination was found to be increased during hypothermia. Dopamine increases pancuronium elimination by an increase in glomerular filtration rate. The dopamine-induced decrease in tubular solute reabsorption did not enhance the elimination of pancuronium.

Different results in cardiopulmonary exercise tests after long-term treatment with felodipine and enalapril in patients with congestive heart failure due to ischaemic heart disease.

We evaluated the cardiopulmonary exercise test results before and after long-term (16 weeks) treatment with the dihydropyridine calcium antagonist, felodipine (10 mg b.i.d., n = 9), and the ACE inhibitor, enalapril (10 mg b.i.d., n = 11), in 20 patients with New York Heart Association class III congestive heart failure. There were no significant differences at baseline. After 16 weeks patients in the enalapril group showed a significant increase in exercise duration and VO2max, without changes in arterial pressures and heart rate. In the felodipine group, exercise duration and VO2max did not change significantly, but arterial pressures and heart rate were significantly reduced at all exercise levels. Between group analysis showed a significant reduction in arterial pressures and heart rate in the felodipine group compared with enalapril, but no differences in aerobic capacity and exercise duration. These results demonstrate that felodipine and enalapril have essentially different effects on cardiopulmonary exercise results in patients with congestive heart failure.

Pharmacokinetics of carboplatin at a dose of 750 mg m-2 divided over three consecutive days.

Pharmacokinetics of the cisplatin analogue carboplatin were studied in patients with disseminated ovarian and testicular cancer. Carboplatin 750 mg m-2 divided over three consecutive days was given as part of an ablative combination regimen followed by autologous bone marrow transplantation. Platinum (Pt) in plasma, plasma ultrafiltrate and urine was determined up to 96 h after the last drug dose by atomic absorption spectrometry. Carboplatin was measured by high performance liquid chromatography. The curves of ultrafiltrated Pt and carboplatin decayed in a bio-exponential way with t1/2 alpha of respectively 65 and 70 min and t1/2 beta of respectively 378 and 1014 min. The volumes of distribution (Vdss) were 18 and 25 l m-2, respectively, and total body clearances (ClTB) 79 and 65 ml min-1 m-2. Both curves overlapped when corrected for the Pt content of carboplatin. A diversion with the three-exponential curve of total Pt occurred between 3 and 6 h. After 10 h approximately 30% of the plasma Pt was protein bound. Total Pt had a larger Vdss (117 l m-2) and a lower total body clearance (14 ml min-1 m-2) than free Pt and carboplatin. Fifty-three per cent of the i.v. administered carboplatin was excreted in the urine in the first 6 h. Plasma ultrafiltrated Pt and carboplatin decreased to undetectable levels within 48 h, but total Pt was detectable until 96 h after the last carboplatin dose. However, this Pt is already bound to protein and unlikely to be cytotoxic to reinfused haemopoietic stem cells, so bone marrow reinfusion can be safely performed at 48 h after repeated dosing of carboplatin on three consecutive days.

Digoxin infusion versus bolus injection in rapid atrial fibrillation: relation between serum level and response.

Using available data on time-concentration and time-effect relationships in normal persons the results of infusion of digoxin in various time periods were simulated and compared with administration of digoxin by bolus injections, using a three-compartment pharmacokinetic model to which a separate small side-effect compartment was subsequently added. The validity of the simulations was tested in 11 patients with rapid atrial fibrillation. Serum digoxin concentrations, ventricular rate and side effects were monitored in a double-blind study comparing an infusion of 1.5 mg digoxin over 6 h with administration of three bolus injections of 0.5 mg digoxin 8 h apart. In agreement with the predictions of the model, the maximal fall in ventricular rate was reached after 8-9 h in the infusion group and after 19-20 h in the bolus injection group, without any detectable difference in side effects. There were certain discrepancies between the results of the clinical study and the predictions of the model, e.g. in serum digoxin concentrations, perhaps due to impaired clearance in the patients. However, it is concluded that the tested model is valid in elderly patients with rapid atrial fibrillation.

Plasma concentration-effect relationship of felodipine intravenously in patients with congestive heart failure.

The pharmacodynamics of felodipine were analyzed in patients with congestive heart failure in a randomized, double-blind, placebo-controlled study. Felodipine at a dose of 1 mg (n = 11) or placebo (n = 12) was given intravenously during a 60-min period. Hemodynamic measurements and plasma samples were obtained every 15 min during a 2-hour period. An increase in heart rate (HR, +8%, p less than 0.01) and cardiac output (CO, +36%, p less than 0.001), and a decrease in mean arterial pressure (MAP, -24%, p less than 0.001) and systemic vascular resistance (SVR, -46%, p less than 0.001), were found. Pulmonary artery, right atrial, wedge pressure, and stroke-work index did not change. Linear regression analysis showed a significant correlation between felodipine plasma levels and changes in HR (r = 0.71, p less than 0.05), MAP (r = 0.94, p less than 0.01), CO (r = 0.73, p less than 0.05), and SVR (r = 0.88, p less than 0.01). A strong hyperbolic correlation was demonstrated between individual plasma levels and changes in MAP (r = 0.97, p less than 0.001). Hysteresis analysis showed that plasma levels are directly related to the concentration at the receptor site. A clockwise hysteresis was found in HR, CO, and SVR, but not in MAP. It is concluded that changes in flow and resistance are based on a physiological adjustment, a baroreflex-mediated response to vasodilation induced by felodipine, resulting in MAPs that remain closely related to felodipine plasma levels over a wide range.

Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.

1. In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.

Oral pharmacokinetics of felodipine in patients with congestive heart failure: variable prediction using intravenous data.

Peak and trough concentrations after 8 weeks oral therapy with felodipine, a vasodilating calcium antagonist of the dihydropyridine group, were predicted from intravenous pharmacokinetic data before therapy in 11 patients, randomly allocated to felodipine treatment 10 mg b.i.d., during a placebo controlled study in patients with congestive heart failure. Peak concentrations were well predictable, but trough levels varied between a good agreement in some patients to a large underestimation in others. Predictability was significantly correlated with half life, plasma clearance and distribution volume of the intravenous pharmacokinetic study. After 8 weeks chronic oral therapy no significant differences could be detected between the oral pharmacokinetics of predictable (n = 6) and unpredictable (n = 5) patients. This demonstrates that felodipine kinetics change during felodipine treatment. Differences in the distribution of blood flow before therapy combined with an interindividual variability in blood flow response during therapy is probably responsible for the observed impossibility to calculate trough levels, and thus oral dosage schedules, from intravenous pharmacokinetic data in patients with congestive heart failure.

Efficacy of felodipine in congestive heart failure.

The efficacy of felodipine, a vasodilating calcium antagonist, was analysed in 23 patients with congestive heart failure, New York Heart Association class III, during an 8-week, double-blind, randomized, placebo-controlled, parallel study. After felodipine, exercise duration increased significantly without changes in oxygen consumption. Heart rate, arterial pressures and rate pressure product decreased at similar submaximal exercise levels. Invasive haemodynamics before and after 8 weeks of therapy revealed arterial vasodilation without reflex tachycardia and no significant reduction in right atrial, pulmonary and capillary wedge pressures. Subjective symptom scores improved and side-effects were minor. Fluid retention, as assessed by body weight and ankle circumference did not occur. Felodipine has a beneficial effect in patients with moderately severe heart failure. Further research is necessary to demonstrate its long-term efficacy and safety.

Value of New York Heart Association classification, radionuclide ventriculography, and cardiopulmonary exercise tests for selection of patients for congestive heart failure studies.

To evaluate the necessity of an objective cardiopulmonary exercise test in the selection procedure of patients for heart failure studies, 50 patients with congestive heart failure New York Heart Association (NYHA) class II and III and a left ventricular ejection fraction less than 40% were subjected to a cardiopulmonary exercise test. The results of the exercise test were compared with the independent clinical estimation of NYHA class and data of measurements obtained at rest. The NYHA classification separated the patients with a mild to moderate impairment of aerobic capacity from patients with a moderate to severe impairment of aerobic capacity very well, but 32% of the NYHA class II patients had a near normal aerobic capacity, and 29% of the NYHA class III patients had a very severe impairment of aerobic capacity, more compatible with NYHA class IV. Only data from exercise measurements showed differences between groups. The determination of maximal aerobic capacity for an objective assessment of patients' performance at exercise is necessary for a proper selection procedure of patients for heart failure studies.

Uptake and excretion of vecuronium bromide and pancuronium bromide in the isolated perfused rat liver.

Using the isolated perfused rat liver preparation, the disappearance from the perfusate and the excretion in the bile of vecuronium bromide and pancuronium bromide and their metabolites were followed for 2 h after the addition of 1 mg of either drug to the perfusate. In addition, the rate of change of the hepatic content of these two compounds was calculated by serially subtracting the amount of the compound and the metabolites in the bile and in the perfusate from the dose of drug added to the perfusate. It was found that, whereas the concentration of pancuronium in the perfusate declined slowly and monoexponentially, vercuronium concentration in the perfusate declined rapidly in a biexponential manner. No metabolites of either drug were detected in the perfusate. Approximately 40% of the injected dose of vecuronium was excreted in the bile as unchanged vecuronium and another 30% as the 3-hydroxy metabolite. No other metabolites of vecuronium were found in the bile. In total only about 7% of pancuronium (unchanged) was collected in the bile by the end of the experiment. It is concluded that, in comparison to pancuronium, the rat liver takes up large amounts of vecuronium rapidly, half of which is eliminated as unchanged vecuronium and half as the 3-hydroxy derivative. A small amount of vecuronium or its 3-hydroxy metabolite is returned to the perfusate from the liver. Some possible mechanisms underlying these differences are discussed.

Pharmacokinetic analyses with RUGFIT: an interactive pharmacokinetic computer program.

RUGFIT is an interactive computer program to fit polyexponential equations to experimental points without the need of assumptions about the number of exponential terms and without the need of initial parameter estimates. The fitting is performed by iterative stripping minimizing the sum of squared residuals. This procedure leads to multiple model equations describing the profile of the y-value in time, that are compared with the test of Boxenbaum et al. The examples analysed in this paper are: a plasma decay curve after an intravenous bolus injection and one after an oral gift, a dA/dt versus time curve with a lag time and a curve possibly reflecting an entero-hepatic recirculation. The outcomes are, where possible, compared with the outcomes obtained with the computer programs CFT3, NONLIN, and NONLINEAR (SPSS). The latter three programs sometimes run into a local minimum, as the outcomes obtained with RUGFIT were close to the best ones obtained with the other programs. The analyses with RUGFIT show that a choice of an inadequate model equation can lead to a marked error in the value of the area under the curve that may result in a marked error of, for instance, the bioavailability. The procedures of RUGFIT are illustrated in the Appendix. RUGFIT also contains options to calculate microparameters, to simulate dosage regimes, to calculate exponents and intercepts from rate constants and to analyse time effect relationships.

Pharmacokinetics and pharmacodynamics of 2,4-diaminopyridine in the cat.

The pharmacokinetics, antagonistic effects, and cardiovascular effects of 2,4-diaminopyridine (2,4-DAP) were studied in 7 anaesthetized cats. Cats received a pancuronium infusion at a constant rate to cause a 90% block of contraction of the anterior tibialis muscle, stimulated through the sciatic nerve. After steady state was reached, 2,4-DAP (750 micrograms/kg IV) was administered. Plasma, urine, and bile were collected over 8 h and analyzed by means of an HPLC assay. Plasma concentrations decreased biexponentially with half-lives of 9.0 +/- 5.7 min and 140 +/- 36 min, respectively. The volume of the central compartment was 0.85 +/- 0.27 L/kg, and the volume of distribution in the steady state was 3.1 +/- 1.1 L/kg. Total plasma clearance was 18 +/- 5 ml/kg/min. Ninety percent of the administered dose was recovered in the urine and 0.1 percent in the bile in 8 h. The antagonism of the pancuronium-induced steady-state block was 98% +/- 5%, with onset and duration of 3.5 +/- 2 min and 165 +/- 40 min, respectively.

Digoxin-felodipine interaction in patients with congestive heart failure.

A possible interaction between felodipine and digoxin was studied in 23 patients with congestive heart failure before and after 8 weeks treatment with both drugs. A modest, non-significant increase in serum digoxin level 2 h postdose (+15%) was found in the felodipine group (n = 11) compared to placebo (n = 12), with no change in the trough and 6 h postdose levels. There was a bimodal distribution of the observed changes in serum digoxin level 2 h postdose: a significant increase (p less than 0.001) was observed only in patients with a high plasma felodipine level, which may have been caused by changes in the absorption rate in those patients. Changes in the elimination of digoxin after felodipine therapy appeared unlikely, since the trough and 6 h post-dose levels were unchanged. Analysis of the clinical characteristics, haemodynamics and laboratory values revealed no significant differences between the subgroups. The observed increase in serum digoxin warrants monitoring the trough and peak levels digoxin in patients with congestive heart failure who are also being treated with felodipine.

Pharmacokinetics of galanthamine (a long-acting anticholinesterase drug) in anaesthetized patients.

The pharmacokinetics of the long-acting anticholinesterase drug, galanthamine, were investigated in eight patients. After i.v. injection of 0.3 mg kg-1, the decrease in the serum concentration of galanthamine followed a biexponential curve. The serum concentration decreased rapidly from 543 +/- 47 ng ml-1 to 128 +/- 14 ng ml-1 between 2 and 30 min with a T1/2 alpha of 6.42 +/- 2.15 min, and then declined more slowly with a T1/2 beta of 264 +/- 28 min. Total serum clearance of galanthamine amounted to 5.37 +/- 0.87 ml min-1 kg-1, and the renal clearance was 1.36 +/- 0.10 ml min-1 kg-1. The cumulative urinary excretion of galanthamine between 0 and 48 h after injection amounted to 28.0 +/- 5.4% of the administered dose. The biliary excretion of galanthamine during 24 h amounted to 0.2 +/- 0.1% of the dose. There was no evidence of glucuronide or sulphate conjugation of galanthamine.

Hepatobiliary disposition of vecuronium bromide in man.

The plasma and bile concentrations, the biliary excretion and the neuromuscular blocking effect of vecuronium bromide were studied during surgery in 13 patients who had received 150 micrograms kg-1 i.v. The amount of vecuronium in liver biopsies taken after i.v injection was measured in a separate group of six patients. Vecuronium appeared early in the bile, in concentrations that were 30-50 times greater than those in the plasma. On the basis of the measured amount of vecuronium excreted in the bile, together with the accepted average daily bile flow, it was estimated that more than 40% of vecuronium was excreted in the bile in 24 h. Liver biopsies indicated that the liver may contain more than 50% of the i.v. dose 30 min after injection. The large distribution of vecuronium into the liver may account for the initial rapid decline in vecuronium plasma concentration and its relatively short duration of action. In this study, neuromuscular blockade was prolonged, possibly as a result of interference, by surgical manipulation, with the rapid hepatic uptake of vecuronium.