Changes in lignocaine disposition during long-term infusion in patients with acute ventricular arrhythmias

Lignocaine disposition was studied in 30 patients with acute ventricular arrhythmias. Serum concentrations of lignocaine, its metabolites Monoethylglycine xylidide (MEGX) and glycine xylidide (GX), and alpha 1-acid glycoprotein (AAG) were analyzed during and after a 48-h lignocaine infusion. AAG concentrations tended to rise in patients with acute myocardial infarction (AMI), leading to binding of the drug in plasma. Lignocaine clearance was estimated at various times during the infusion using a Bayesian parameter estimation program and was found to decline over the course of the infusion. There was a significant reduction in clearance based on estimates obtained at the end of the infusion compared with estimates obtained during the first 0-5 h. Clearance was reduced both in patients who had an AMI and those who did not. Multiple linear regression analysis of the clearance data revealed that these changes could be described by a linear function of time and AAG concentration. These findings suggest that other factors in addition to protein binding changes may influence lignocaine disposition during long-term infusion.     

Clinical pharmacokinetics of beta-adrenoceptor antagonists. An update

The beta-adrenoceptor antagonists have been widely used clinically for over 20 years and their pharmacokinetics have been more thoroughly investigated than any other group of drugs. Their various lipid solubilities are associated with differences in absorption, distribution and excretion. All are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug. Because satisfactory plasma concentration effect relationships have been difficult to establish for most clinical indications, and little dose-related toxicity is seen, plasma beta-adrenoceptor antagonist concentration measurement is usually unnecessary. The investigation of the clinical pharmacokinetics of the beta-adrenoceptor antagonists has added greatly to our theoretical and practical knowledge of pharmacokinetics and made some contribution to their better clinical use.     

Influence of lignocaine on plasma protein binding and pharmacokinetics of verapamil in dogs

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

Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein

AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.     

The effects of age and smoking on the plasma protein binding of lignocaine and diazepam.

In 63 healthy ambulant subjects 18 to 88 years of age, the plasma protein binding of diazepam (principally bound to albumin) decreased with age. Diazepam binding in plasma correlated positively with plasma albumin concentration which also decreased with age. In contrast, the plasma protein binding of the basic drug, lignocaine (predominantly bound to alpha 1-acid glycoprotein [AAG]), tended to increase slightly with age. Lignocaine binding in plasma correlated positively with plasma AAG concentration which also increased slightly with age. Smoking did not affect the plasma protein binding of diazepam or lignocaine or the plasma concentrations of albumin, AAG or nonesterified fatty acids. These results suggest that age-related changes in plasma protein binding of lignocaine and diazepam are determined in part by age-related changes in the concentrations of the binding proteins in plasma. The ageing process alone causes only small changes in the plasma protein binding of these drugs compared with the effect of disease states, however.     

On the role of alpha 1-acid glycoprotein in lignocaine accumulation following myocardial infarction.

1 Blood plasma and free lignocaine concentrations have been measured 12 h after beginning a constant infusion of 2 mg/min and again at the end of the infusion (36-72 h) in five patients with myocardial infarction (MI) and compared with five control patients who did not develop objective evidence of MI. 2 In MI patients, total plasma concentration rose significantly between 12 h and the end of infusion. Because of an increase in alpha 1 acid glycoprotein (AAG) plasma binding increased, so that free drug concentration did not change. The rise in whole blood concentration was less than that in plasma as a result of drug redistribution out of red cells due to enhanced binding. 3 In control patients, neither blood nor plasma concentrations changed with time and plasma binding remained constant. Free drug concentrations, however, rose slightly. 4 The concentrations of GX and MEGX remained unchanged in all patients, but the ratio of lignocaine/MEGX concentrations fell in controls but rose in MI patients. 5 Pharmacokinetic modelling suggested that at least some of the rise in blood lignocaine concentration was due to reduced clearance resulting from enhanced plasma binding. 6 We conclude that the rise in AAG following MI is responsible for increased plasma binding and drug redistribution within blood. These changes, together with a reduction in lignocaine clearance, can explain much of the phenomenon of lignocaine accumulation in MI.     

Lignocaine disposition in blood in epilepsy.

1 The plasma concentration of alpha 1-acid glycoprotein (AAG) was significantly greater in 27 epileptic subjects receiving anticonvulsants compared with 27 age- and sex-matched drug-free control subjects. 2 Increased AAG concentration was associated with enhanced lignocaine binding in the plasma of epileptics. 3 Increased AAG concentration was also associated with a redistribution of lignocaine out of red cells and into plasma thus lowering the blood to plasma concentration ratio. 4 Enhanced lignocaine binding in epileptics receiving anticonvulsant therapy may result in lower free (unbound) plasma concentrations of the drug compared to normal subjects with equivalent total plasma lignocaine concentrations.     

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infusion in man and in vitro studies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine. MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120 mg, MEGX HCl 120 mg, lignocaine HCl 120 mg + MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (Vss), and half-life values were calculated and compared by paired t-test. Systolic time intervals and QT interval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58 +/- 18 to 48 +/- 13 L hr-1 (p less than 0.02). The Vss was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QT interval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.     

Failure of 'therapeutic' doses of beta-adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

The effects of separate 1 week pre-treatments with each of the beta-adrenoceptor antagonists, propranolol (80 mg every 12 h), metoprolol (100 mg every 12 h) and atenolol (50 mg once daily), on the disposition of a single i.v. dose of tolbutamide were studied in six healthy volunteers. In addition, the effects of a 1 week pre-treatment with metoprolol (100 mg every 12 h) and atenolol (50 mg once daily) on the disposition of orally and i.v. administered lignocaine were determined in seven healthy subjects. Tolbutamide clearance, half-life, volume of distribution and plasma protein binding were not altered by the beta-adrenoceptor blocker pre-treatments. Similarly, neither metoprolol nor atenolol had a significant effect on the systemic clearance, apparent oral clearance or other dispositional parameters of lignocaine. 'Therapeutic' plasma concentrations of the beta-adrenoceptor blockers were confirmed on each study day. It is concluded that the inhibition of oxidative drug metabolism previously reported for lipophilic beta-adrenoceptor blockers may be selective for different forms of cytochrome P450 and possible concentration-dependent.     

A free lignocaine index as a guide to unbound drug concentration.

A free lignocaine index was developed on the basis of measurements of plasma lignocaine and its principle binding protein, alpha 1-acid glycoprotein (AAG) in 80 samples from 16 patients admitted to the coronary care unit and given prophylactic lignocaine therapy. The free drug fraction, fu, of lignocaine was determined by equilibrium dialysis and its relationship to AAG and total lignocaine concentration (T) defined by multiple linear regression analysis as l/fu = 1.45 + 0.023 (AAG) -0.129 (T) (multiple r = 0.872, P less than 0.001). This relationship was used to calculate the 'free lignocaine index' as fu X T and compared with the observed value obtained by equilibrium dialysis of 178 samples from 41 separate subjects who received lignocaine after suspected myocardial infarction. There was a highly significant relationship (r = 0.933, n = 178, P less than 0.001) between the observed and predicted values. We conclude that the free drug index may be useful in rapidly assessing the unbound (free) concentration of lignocaine in plasma.     

Enzyme induction with rifampicin; lipoproteins and drug binding to alpha 1-acid glycoprotein

Hepatic enzyme induction has been reported to increase lignocaine binding, alpha 1-acid glycoprotein concentration and high density lipoprotein (HDL) cholesterol. In eight volunteers treated with rifampicin for 3 weeks there was no significant alteration in these three variables although their antipyrine clearance was significantly increased. In 10 patients with pulmonary tuberculosis treated with rifampicin (mean 5 months) the degree of serum protein binding of lignocaine, alpha 1-acid glycoprotein and HDL-cholesterol concentration was not different from that of matched control patients. These results suggest that differential induction of these variables may occur.     

Amlodipine: pharmacokinetic profile of a low-clearance calcium antagonist

Structural features of amlodipine give the molecule physicochemical and pharmacokinetic properties that are unique among calcium antagonists. Amlodipine is absorbed gradually after oral administration (peak plasma levels 6-12 h postdose) and has an absolute bioavailability of 64%. Low clearance and a high volume of distribution give amlodipine a long elimination half-life, and mean effective plasma levels are maintained with once-daily doses. With repeated once-daily dosing, the steady state is achieved after the seventh to ninth dose. The pharmacokinetic properties of amlodipine avoid the sharp fluctuations in plasma level seen with other calcium antagonists that are associated with vasodilatation-induced side effects such as tachycardia, headache, and flushing. The pharmacokinetics of amlodipine are not significantly altered in elderly or renally impaired patients, but there is reduced clearance in patients with hepatic impairment. There are no pharmacokinetic interactions between amlodipine and cimetidine or digoxin.     

Steady-state pharmacokinetics of (R)- and (S)-methadone in methadone maintenance patients

AIMS: To investigate the steady-state pharmacokinetics of (R)- and (S)-methadone in a methadone maintenance population. METHODS: Eighteen patients recruited from a public methadone maintenance program underwent an interdosing interval pharmacokinetic study. Plasma and urine samples were collected and analysed for methadone and its major metabolite (EDDP) using stereoselective h.p.l.c. Methadone plasma protein binding was examined using ultrafiltration, and plasma alpha1-acid glycoprotein concentrations were quantified by radial immunoassay. RESULTS: (R)-methadone had a significantly (P < 0.05) greater unbound fraction (mean 173%) and total renal clearance (182%) compared with (S)-methadone, while maximum measured plasma concentrations (83%) and apparent partial clearance of methadone to EDDP (76%) were significantly (P < 0.001) lower. When protein binding was considered (R)-methadone plasma clearance of the unbound fraction (59%) and apparent partial intrinsic clearance to EDDP (44%) were significantly (P < 0.01) lower than for (S)-methadone, while AUCtau_?u?ss (167%) was significantly (P < 0. 001) greater. There were no significant (P > 0.2) differences between the methadone enantiomers for AUCtauss, steady-state plasma clearance, trough plasma concentrations and unbound renal clearance. Patients excreted significantly (P < 0.0001) more (R)-methadone and (S)-EDDP than the corresponding enantiomers. Considerable interindividual variability was observed for the pharmacokinetic parameters, with coefficients of variation of up to 70%. CONCLUSIONS: Steady-state pharmacokinetics of unbound methadone are stereoselective, and there is large interindividual variability consistent with CYP3A4 mediated metabolism to the major metabolite EDDP; the variability did not obscure a significant dose-plasma concentration relationship. Stereoselective differences in the pharmacokinetics of methadone may have important implications for pharmacokinetic-pharmacodynamic modelling but is unlikely to be important for therapeutic drug monitoring of methadone, in the setting of opioid dependence.     

Clinical pharmacokinetics of verapamil, nifedipine and diltiazem

The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacokinetics and metabolism of the proton pump inhibitor pantoprazole in man

Pantoprazole, a second-generation proton pump inhibitor, is absorbed after oral administration as enteric-coated tablet with maximum plasma concentrations within 2-3 h and a bioavailability of 77%. Food has no relevant effect on absorption. The pharmacokinetics of pantoprazole are dose linear in the therapeutic range. The parent drug is totally metabolized, mainly by the polymorphically expressed CYP2C19 and by CYP3A. The pharmacokinetic profile is practically unchanged after multiple dosing, as is expected for a drug with a short half-life of about 1 h. A lack of pharmacokinetic interactions with various drugs has been shown. No clinically relevant changes in the pharmacokinetics of pantoprazole are observed in elderly subjects and patients with severe renal insufficiency. However, clearance is decreased in poor metabolizers of (S)-mephenytoin and in patients with liver cirrhosis.     

Pharmacokinetics of CM 57755, a new histamine H2-receptor antagonist, after single oral doses in man

The plasma pharmacokinetics and urinary excretion of CM 57755, an H2-receptor antagonist, were studied after administration of single oral doses in a range between a 100 and 700 mg in human volunteers. Pharmacokinetic parameters were calculated model-independent. Absorption of CM 57755 was bimodal and the maximum plasma concentration was reached between 2 and 4 h after dosing. The drug was widely distributed with an apparent volume of distribution between 140 and 200 l. The plasma clearance was between 56 and 69 L/h. The plasma concentrations declined following a monoexponential function with an elimination half-life of 2 h. No modification in the plasma clearance or other pharmacokinetic parameters with these doses was observed. Therefore, a linear pharmacokinetic profile of CM 57755 was proposed. About 40% of the parent drug was unchanged in urine excreted over the 24 h. The drug was compared with cimetidine and ranitidine, the three compounds seemed to exhibit a consistent pharmacokinetic profile.     

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infustion in man and in vitrostudies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine, MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120mg, MEGX HCl 120 mg, lignocaine HCl 120 mg+MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (V _ss ), andhalf-life values were calculated and compared by paired t-test. Systolic time intervals and QTinterval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58±18 to 48±13 L hr(su–1) (p <0.02). The V(inss) was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QTinterval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.     

Reduction of oral bioavailability of lignocaine by induction of first pass metabolism in epileptic patients.

1. The pharmacokinetics of lignocaine following single oral and intravenous doses have been investigated in six normal volunteers and in six patients receiving chronic antiepileptic drug therapy. 2. After intravenous administration, serum lignocaine levels declined biexponentially in all subjects. The serum clearance (mean +/- s.d.) was slightly higher in the patients (0.85 +/- 0.09 v 0.77 +/- 0.07 l/min) but the difference was not statistically significant. 3. Lignocaine bioavailability after oral administration was more than two-fold in the patients than in the normal subjects (0.15 +/- 0.06 v 0.37 +/- 0.09, P < 0.001). 4. It is suggested that the reduced bioavailability of lignocaine in the patients is a consequence of stimulation of hepatic first-pass metabolism by antiepileptic drugs.     

Factors affecting free (unbound) lignocaine concentration in suspected acute myocardial infarction.

1. Free plasma lignocaine concentrations were measured for up to 48 h after constant infusion of the drug in 41 subjects with suspected acute myocardial infarction. 2. The free plasma lignocaine clearance at 12 h was significantly and proportionately related to body weight and to the presence of mild (Killip Class II) heart failure, with an 18% reduction in free clearance in the latter condition. 3. The free plasma lignocaine was not related to sex, age or the presence of confirmed acute myocardial infarction, when corrected for the effects of body weight and presence of heart failure. 4. Free plasma lignocaine concentration 1 h after a fixed loading dose were also significantly related to body weight and presence of heart failure but not to sex, age or proven acute myocardial infarction. 5. The data indicate that correction of loading and maintenance infusion for body weight and presence of (even mild) heart failure should somewhat reduce variability in free (and presumably active) plasma lignocaine concentrations but that the free plasma lignocaine concentration at 12 h is most accurately predicted by measuring the free (and to a lesser extent total) plasma lignocaine concentration at 1 h.     

Clinical pharmacokinetics of disopyramide

Disopyramide is an antiarrhythmic agent with proven efficacy in the management of atrial and ventricular arrhythmias. The drug is well absorbed and undergoes virtually no first-pass metabolism. Peak concentrations are achieved approximately 0.5 to 3.0 hours after a dose. Absorption is reduced and slightly slowed in patients with acute myocardial infarction. Disopyramide is excreted as unchanged drug (two-thirds) or as the metabolite mono-N-desisopropyldisopyramide, with elimination via both renal and biliary routes. Elimination half-life is approximately 7 hours in normal subjects and patients, but is prolonged in patients with renal insufficiency (creatinine clearance less than 60 ml/min). Disopyramide exhibits complex protein binding. It is bound to alpha 1-acid glycoprotein (AAG), an acute phase reactant, and binds in a concentration-dependent (saturable) manner. The unbound fraction is reduced in the presence of elevated concentrations of AAG, as are found in acute myocardial infarction and in some chronic haemodialysis patients and renal transplant recipients. Free disopyramide concentrations are low relative to total concentration in these patients. Because the pharmacological effects of disopyramide are determined by unbound drug, changes in the unbound fraction could make total disopyramide concentrations misleading as a guide to therapy. Changes in protein binding do not, however, alter free disopyramide or metabolite concentrations, both of which are dependent only on dosage and intrinsic clearance. Free drug concentration measurement could potentially improve therapeutic monitoring, but is as yet of unproven clinical value. Disopyramide is cleared more rapidly in children than in adults, and therefore children require higher dosages to attain therapeutic concentrations.