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.     

Effect of the CYP3A4 inhibitor erythromycin on the pharmacokinetics of lignocaine and its pharmacologically active metabolites in subjects with normal and impaired liver function

AIMS: The objectives of this study were: (i) to evaluate the effect of a cytochrome P450 (CYP) 3A4 inhibitor, erythromycin, on the pharmacokinetics of intravenous lignocaine and its two pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX); (ii) to assess whether the effects of the erythromycin inhibitory action on lignocaine clearance and the results of the MEGX liver function test depend on liver functional status; and (iii) to determine the effects of both moderate and severe liver dysfunction on the disposition kinetics of lignocaine. METHODS: The study was carried out on 10 healthy volunteers, and 10 Child's class A and 10 class C cirrhotic patients, according to a double-blind, randomized, two-way crossover design. On day 1 of the investigation, all subjects received three oral doses of erythromycin (600 mg of the ethylsuccinate ester) or placebo, and two further doses on day 2. One hour after the fourth dose, subjects were given 1 mg kg-1 lignocaine intravenously. Timed plasma samples were then obtained until 12 h for determination of the concentrations of lignocaine, MEGX and GX. RESULTS: Erythromycin caused statistically significant, although limited, modifications of lignocaine and MEGX pharmacokinetic parameters. In healthy volunteers, lignocaine clearance was decreased from 9.93 to 8.15 ml kg-1 min-1[mean percentage ratio (95% CI), 82 (65-98)] and the half-life was prolonged from 2.23 to 02.80 h [mean percentage ratio (95% CI), 130 (109-151)]; MEGX area under the concentration-time curve from 0 h to 12 h was increased from 665 to 886 ng ml-1 h [mean percentage ratio (95% CI), 129 (102-156)]. Quantitatively similar modifications were observed in the two cirrhotic groups. GX concentrations were lowered in all study groups, although not to statistically significant extents. Erythromycin coadministration caused no appreciable interference with the results of the MEGX test. Only in patients with Child's grade C liver cirrhosis were lignocaine kinetic parameters significantly altered with respect to healthy volunteers. Thus, clearance was approximately halved, steady-state volume of distribution was increased, and terminal half-life was more than doubled. CONCLUSIONS: Although erythromycin only modestly decreases lignocaine clearance, it causes a concomitant elevation of the concentrations of its pharmacologically active metabolite MEGX. A pharmacodynamic study following lignocaine infusion to steady state appears necessary to assess the actual clinical relevance of these combined effects. The degree of liver dysfunction has no influence on the extent of the erythromycin-lignocaine interaction, whereas it markedly influences the extent of the changes in lignocaine pharmacokinetics. These findings indicate that no dose adjustment is needed in patients with moderate liver cirrhosis, whereas the lignocaine dose should be halved in patients with severe cirrhosis.     

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine

Objective: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. Methods: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg · kg⁻¹ was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. Results: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t_1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC_(0–11 h) by 45–60%. Conclusion: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine. Received: 8 January 1998 / Accepted in revised form: 8 June 1998     

The effect of ranitidine on the disposition of lignocaine.

The effect of pretreatment with ranitidine (150 mg twice daily for 5 days) on the disposition of lignocaine was examined in 10 healthy volunteers (five male, five female). Each subject received separate oral (250 mg) and intravenous (1.5 mg/kg) doses of lignocaine hydrochloride before and after ranitidine. Lignocaine systemic clearance was reduced by 9% (1.11 to 0.99 1 h-1 kg-1; P less than 0.01) following ranitidine pretreatment. The volume of distribution at steady-state was reduced by 15% (3.34 to 2.85 1 kg-1; P less than 0.005). Lignocaine oral clearance, elimination half-life and oral bioavailability were unchanged after ranitidine pretreatment. There was no sex difference in the effects of ranitidine pretreatment on lignocaine disposition. These results are consistent with small reductions in blood flow to the splanchnic and other vascular beds due to ranitidine.     

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.     

Lignocaine and indocyanine green kinetics in patients following myocardial infarction.

1. Blood clearances of lignocaine and indocyanine green together with indocyanine green half-lives were measured in 17 post-myocardial infarct patients (one patient was studied twice) between 8 h and 36 h after starting intravenous lignocaine infusions for the treatment of cardiac arrhythmias. 2. Mean +/- s.d. values of lignocaine clearance (ml min-1 kg-1) were higher in patients without heart failure (11.8 +/- 2.6, n = 9) than in those with heart failure (7.2 +/- 1.9, n = 9) (P < 0002). 3. Clearances of lignocaine and indocyanine green were not correlated but lignocaine clearance was directly related to the reciprocal of indocyanine green half-life (rs = 0.67, P < 0.01). 4. In eight patients who received both lignocaine and indocyanine green and in a further five patients received only lignocaine and whose lignocaine infusions lasted 24h or more, a 25% rise in lignocaine concentrations was observed between 8-12h and 24-28h. 5. The mean +/- s.d. post-infusion terminal half-life of lignocaine in four patients whose lignocaine infusions lasted 30h or longer was 7.2 +/- 2.1 h. 6. Heart failure was associated with greater changes in lignocaine kinetics than in indocyanine green kinetics. 72% of the variance between observed and predicted lignocaine clearances could be accounted for by multiple linear regression analysis incorporating indocyanine green half-life and the presence or absence of heart failure. Indocyanine green half-life contributed only 17% of the variance indicating that by itself it is of limited value in predicting lignocaine requirements. 7. Lignocaine kinetics during and after prolonged intravenous infusion were not predicted by data obtained after intravenous bolus injection. 8. A lowering of lignocaine dosage may be clinically desirable in the presence of heart failure and if an infusion lasts longer than 24 h.     

Lignocaine kinetics in cardiac patients and aged subjects.

1 The pharmacokinetics following long term intravenous infusion of lignocaine to cardiac patients have been examined. 2 Plasma levels and half-lives of lignocaine and monoethylglycinexylidide (MEGX) showed wide inter-patient variability. 3 Toxicity reactions to therapy were associated with elevated lignocaine and/or MEGX plasma levels. 4 In a separate study the effect of age on the pharmacokinetics of lignocaine was examined using bolus doses (50 mg) of the drug to young and aged subjects. 5 Elderly subjects had significantly longer half-lives for lignocaine compared to younger individuals although no change in plasma clearance occurred. 6 The drug appeared to distribute differently in the aged as reflected by significantly increased apparent volumes of distribution. 7 The 24 h urinary recovery of the major metabolite (total 4-hydroxyxylidine) showed a significant reduction in the elderly when compared to the young. 8 The clinical significance of these studies with respect to lignocaine therapy has been discussed.     

The impairment of lignocaine clearance by propranolol--major contribution from enzyme inhibition.

To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100-140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/- 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/- 50 s.d.% (P less than 0.025) and it prolonged the elimination half-life of lignocaine by 20 +/- 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/- 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.     

Extrahepatic production of the lignocaine metabolite monoethylglycinexylidide (MEGX).

The extrahepatic production of monoethylglycinexylidide (MEGX) from lignocaine was measured in a 20-year-old female rendered anhepatic while awaiting liver transplantation 4 days after a paracetamol overdose. Following hepatectomy and during continuous arteriovenous dialysis, cardiac stability and control over rising intracranial pressure was restored. Lignocaine (1 mg kg body weight-1 intravenously over 2 min) reached a subtherapeutic peak serum concentration of 0.89 mg l-1 and was rapidly and exponentially cleared, reaching the lower limit of detection after 5 h (cf. around 2 h in normal subjects). There was significant production of MEGX at extrahepatic sites with serum concentrations rising from undetectable levels to 15 micrograms l-1 at 15 min and to a peak of 30 micrograms l-1 at 2 h and falling thereafter. MEGX concentrations were similar in arterial, venous, and pulmonary arterial blood, suggesting minimal MEGX production in the heart, lungs or skeletal muscle. Extrahepatic production of MEGX may contribute to total MEGX formation and should be considered when interpreting test results.     

The effect of liver disease and food on plasma MEGX concentrations.

Plasma monoethylglycinexylidide (MEGX) concentrations were measured in 15 healthy controls (age 23-46 years) and 12 patients with biopsy proven cirrhosis (age 34-70 years) 30 min after 1 mg kg-1 intravenous lignocaine. Mean (+/- s.d.) MEGX concentrations were 57 +/- 33 ng ml-1 in the controls compared with 21 +/- 18 ng ml-1 in the cirrhotics (P < 0.05), but there was overlap in the range of concentrations. MEGX concentrations were inversely correlated with age, but not disease severity, in the cirrhotic patients (r = 0.62, P = 0.04) but not in the control subjects. In a second study 20 healthy subjects were given 1 mg kg-1 intravenous lignocaine on two occasions; either fed or fasted, and samples taken at 15, 30 and 60 min after dosage. MEGX concentrations were not significantly different at any time within either day or between fed and fasted study days. There was no correlation with age. The plasma lignocaine concentration at 15 min was significantly higher fed than fasted (2.88 +/- 2.44 and 1.82 +/- 0.96 micrograms ml-1, P = 0.01). Measurement of plasma MEGX after i.v. lignocaine is a useful test of liver function and may be performed in fed or fasted subjects. It is reproducible within an individual but is not specific for cirrhosis and appears age-related in liver disease.     

Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.

1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and biotransformation of the cyclosporine metabolite M-17 in the rabbit

The monohydroxylated cyclosporine (CsA) metabolite M-17 was isolated from bile of human liver transplant recipients by preparative HPLC. The structure and purity of the metabolite were confirmed by fast atom bombardment-mass spectroscopy and proton NMR. The isolated metabolite was administered iv to three rabbits at a dose of 1.0 mg/kg with the following mean pharmacokinetic parameters being determined: half-life (t1/2B) 2.22 hr, volume of distribution (Vss) 1.44 liters/kg, and clearance 11.07 ml/min/kg. These are not significantly different from those obtained for CsA. In bile and urine obtained from rabbits administered M-17, the CsA metabolites M-8, M-18, and M-26 were found, indicating that M-17 is further metabolized. The latter data support the proposed biotransformation pathways for M-17.     

Pharmacokinetics of chlordesmethyldiazepam after single-dose oral administration in humans

The pharmacokinetics of chlordemethyldiazepam--a pharmacologically very active new 1,4-benzodiazepine derivative--in healthy subjects after administration of a single oral dose of 2 mg, was studied. Peak concentrations were reached in 1.2 +/- 0.2 hours. Plasma levels declined with a biphasic pattern, and the elimination phase had a half-life of 82.9 +/- 14.1 hours. The concentrations of the main metabolite of chlordemethyldiazepam, lorazepam, were about 7% of those of the parent compound. In urine only conjugated lorazepam could be found its 96 hour excretion reaching about 15% of the administered dose of parent drug.     

CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in patients with liver and kidney diseases and epileptic patients.

1. The in vitro hepatic metabolism of lignocaine to monoethylglycinexylide (MEGX) is mediated by CYP3A4 and that of coumarin to 7-hydroxycoumarin (7OHC) by CYP2A6. We investigated the usefulness of monitoring serum MEGX concentrations (after 1 mg kg-1 lignocaine i.v.) and urinary 7OHC excretion (after 5 mg coumarin p.o.) to reflect liver function in patients with liver (n = 36), kidney (n = 12) and epileptic (n = 12) disease and in control subjects (n = 20). The extent of liver disease was assessed using measurements of serum aminoterminal propeptide (PIIINP) and Child-Pugh grades. 2. Serum concentrations of MEGX were decreased in severe (4.6 +/- 3.0 s.d. ng ml-1), moderate (19.1 +/- 11.6 s.d. ng ml-1) and mild (32.8 +/- 14.2 s.d ng ml-1) liver disease as compared with controls (53.4 +/- 15.8 s.d ng ml-1). The excretion of 7OHC over 2 h was decreased in severe (18.0 +/- 10.3 s.d % of dose) and moderate (34.2 +/- 15.6 s.d %), but not in mild (49.7 +/- 19.0 s.d %) liver disease as compared with that in controls (56.2 +/- 11.6%). 3. In epileptic patients the urinary recovery of 7OHC was increased (2 h value 69.5 +/- 13.2 s.d %) suggesting enzyme induction. In contrast, serum MEGX concentration were low (40.0 +/- 14.1 s.d ng ml-1), possibly due to competition for CYP3A4 between lignocaine and antiepileptic drugs. 4. In patients with kidney disease serum MEGX concentration (56.5 +/- 26.1 s.d ng ml-1) was similar to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pharmacokinetics of lignocaine and beta-adrenoceptor antagonists in patients with acute myocardial infarction

Lignocaine (lidocaine) and beta-adrenoceptor antagonists are widely used after acute myocardial infarction. The therapeutic value of these agents depends on the achievement and maintenance of safe and effective plasma concentrations. Lignocaine pharmacokinetics after acute myocardial infarction (MI) are controlled by a number of variables. The single most important is left ventricular function, which affects both volume of distribution and plasma clearance. Other major factors include bodyweight, age, hepatic function, the presence of obesity, and concomitant drug therapy. Lignocaine is extensively bound to alpha 1-acid glycoprotein, a plasma protein which is also an acute phase reactant. Increases in alpha 1-acid glycoprotein concentration occur after an acute MI, decreasing the free fraction of lignocaine in the plasma and consequently decreasing total plasma lignocaine clearance without altering the clearance of non-protein-bound lignocaine. Complex changes in lignocaine disposition occur with long term infusions, and therefore early discontinuation of lignocaine infusions (within 24 hours) should be undertaken whenever possible. Because the risk of ventricular tachyarrhythmia declines rapidly after the onset of an acute MI, lignocaine therapy can be rationally discontinued within 24 hours in most patients. Lignocaine has a narrow toxic/therapeutic index, so that pharmacokinetic factors are critical in dose selection. In contrast, beta-adrenoceptor antagonists' adverse effects are more related to the presence of predisposing conditions (such as asthma, heart failure, bradyarrhythmias, etc.) than to plasma concentration. The pharmacokinetics of beta-adrenoceptor antagonists are important to help assure therapeutic efficacy, to provide information about the anticipated time course of drug action, and to predict the possible role of ancillary drug effects (such as direct membrane action) and loss of cardioselectivity. Lipid solubility is the main determinant of the pharmacokinetic properties of a beta-adrenoceptor antagonist. Lipid-soluble agents like propranolol and metoprolol are well absorbed orally, and undergo rapid hepatic metabolism, with important presystemic clearance and a short plasma half-life. Water-soluble drugs like sotalol, atenolol, and nadolol are less well absorbed, and are eliminated more slowly by renal excretion. Clinical assessment of beta-adrenoceptor antagonism is more valuable than plasma concentration determinations in evaluating the adequacy of the dose of a particular beta-adrenoceptor antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of phenobarbital on the pharmacokinetics of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine

The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values +/- SD = 220.2 +/- 63.5 versus 112.5 +/- 46.0 ml/h/kg, p less than 0.007) and a significantly shorter plasma half-life (mean values +/- SD = 4.3 +/- 1.0 versus 6.7 +/- 0.8 h, p less than 0.0015). These results suggest that PB induces CBZ-E metabolism.     

The pharmacokinetics of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) in Sprague-Dawley rats

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.     

Correlation between midazolam and lignocaine pharmacokinetics and MEGX formation in healthy volunteers

AIMS: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. METHODS: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. RESULTS: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively. CONCLUSIONS: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.     

Effect of lignocaine on arginine-vasopressin plasma levels: baseline or induced by frusemide.

1. To assess whether or not lignocaine influences baseline and frusemide-induced (5 mg kg-1) plasma concentrations of arginine-vasopressin (AVP), 2 groups of rabbits received an infusion of lignocaine (130 micrograms min-1 kg-1) for 6 h. Lignocaine-induced changes in AVP plasma concentrations were substantiated by measurement of diuresis and natriuresis and hepatic plasma flow, by means of an infusion of indocyanine green (ICG) (249 micrograms min-1 kg-1). 2. Baseline plasma AVP levels were 4.9 +/- 0.9 pg ml-1 (+/- s.e.), and following lignocaine, these values were reduced to 0.7 +/- 0.1 pg ml-1 (P less than 0.01). Frusemide increased AVP levels to 134.1 +/- 73.6 pg ml-1 (P less than 0.05) and lignocaine totally prevented this increase, e.g. mean AVP levels of 2.7 pg ml-1. 3. Lignocaine enhanced baseline diuresis secondary to an increase in free water clearance; none of the experimental conditions affected the diuresis and natriuresis induced by frusemide. 4. Frusemide reduced the hepatic plasma flow and this decrease was not reversed by the infusion of lignocaine. 5. It is concluded that in healthy rabbits lignocaine reduces baseline secretion of AVP and its antidiuretic effect; in addition, lignocaine prevents the rise in AVP induced by frusemide.     

Pharmacokinetics of 4-hydroxycyclophosphamide and metabolites in the rat.

Pharmacokinetics of 4-hydroxycyclophosphamide (4-OHCP), the major active microsomal metabolite of cyclophosphamide (CP), were investigated in the Sprague-Dawley rat following separate iv bolus administrations of CP, synthetic 4-OHCP, and their combination. CP, 4-OHCP, and other metabolites such as phosphoramide mustard, alcophosphamide, and 3-(2-chloroethyl)-1,3-oxazolidin-2-one in rat plasma were simultaneously analyzed using GC/MS and stable isotope dilution techniques. Following iv administrations of 4-OHCP to rats at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg, phosphoramide mustard was found to be the major circulating metabolite followed by alcophosphamide and 3-(2-chloroethyl)-1,3-oxazolidin-2-one. No appreciable amount of nor-nitrogen mustard was detected in circulation. The mean excretion of unchanged 4-OHCP in two rats was 4.1 +/- 0.2% of the administered dose in 24-hr urine. Plasma concentration-time profiles of 4-OHCP declined monoexponentially with a mean half-life and total plasma clearance values of 8.1 min and 81.2 ml/min.kg, respectively. No dose-dependent kinetics were apparent between the 10 and 40 mg/kg doses used. The short half-life of 4-OHCP may be due partly to its degradation in plasma, which was found to be a first-order process in vitro with a half-life of 5.2 min. On the other hand, when CP was administrated to eight separate rats at 20 mg/kg each, the mean apparent elimination half-life for the derived 4-OHCP was 55.4 min as compared to 58.2 min, the mean elimination half-life for the parent drug.(ABSTRACT TRUNCATED AT 250 WORDS)