A study of the transport of lithium across the erythrocyte membrane in vivo and of the effects of the ion transport inhibitors digoxin and dipyridamole.

1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two-compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway.     

Lack of effect of amisulpride on the pharmacokinetics and safety of lithium

Lithium may be used as adjuvant therapy in schizophrenic patients and antipsychotics can be employed during the early phases of lithium therapy in patients with bipolar disorder. The issue of interactions between lithium and antipsychotics is therefore important. This study investigates the potential influence of repeated administration of amisulpride, an atypical antipsychotic, on the pharmacokinetics of lithium at steady state. Twenty-four healthy male volunteers (aged 1833 yr) received lithium carbonate (500 mg b.i.d.) for 14 d. All subjects were shown to have stable lithium serum concentrations after 57 d and were then randomized to receive double-blind administration of amisulpride (100 mg b.i.d.) or placebo bid from day 8 of lithium administration. Complete pharmacokinetic profiles were obtained on days 7 and 14 for lithium and trough plasma concentrations on days 10, 12 and 14 for amisulpride. Co-administration of amisulpride appeared to exert no effect on the pharmacokinetics of lithium. All treatments were well tolerated and safety assessment revealed no differences between the lithium+placebo and lithium+amisulpride groups. This finding permits the flexible use of amisulpride in patients already receiving lithium therapy.     

Lithium does not alter the renal response to a pressor dose of tyramine in man.

Renal clearance of lithium has been used as a marker of proximal tubular function in man. Recently, lithium pre-treatment has been shown to interfere with the natriuretic actions of some natriuretic agents in man. We have therefore investigated the effects of oral lithium carbonate (500 mg) on the natriuretic response to a pressor dose of tyramine (15 micrograms kg-1 min-1) in six normal volunteers. Lithium had no effect on baseline sodium excretion, nor did it affect the tyramine-induced increase in blood pressure and subsequent natriuresis. These results show that oral lithium carbonate (500 mg) does not appear to interfere with the pressure natriuretic response to tyramine in man.     

Effect of ibuprofen on lithium plasma and red blood cell concentrations

The effect of ibuprofen on steady-state lithium plasma and red blood cell concentrations was studied in 11 normal volunteers. During the seven-day control phase, sustained-release lithium carbonate 450 mg was administered every 12 hours. Lithium plasma and red blood cell concentrations were determined on days 5, 6, and 7. During the treatment phase (days 7-15), ibuprofen 400 mg was administered four times a day concurrently with lithium. Lithium plasma and red blood cell concentrations were obtained on days 14, 15, and 16. Multiple blood samples were obtained over a 12-hour period on days 6 and 15. Urine samples were collected from six subjects. The mean minimum lithium concentration increased 15% when ibuprofen was added. Mean maximum lithium concentration, area under the curve, red blood cell concentrations, and the lithium red blood cell to plasma ratio were significantly higher during the treatment phase. Mean lithium total body and renal clearance values were significantly lower during the treatment with ibuprofen. The administration of ibuprofen can increase steady-state plasma lithium concentrations and decrease lithium clearance.     

Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses

Summary A gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorthalidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n=10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those predicted from the single oral dose studies in healthy volunteers.A preliminary report of this paper was presented at the Ann. Meet. Sw. Med. Soc. Nov. 1973Supported by a Geigy scholarship     

Importance of “first-pass elimination” for interindividual differences in steady-state concentrations of the adrenergicβ-receptor antagonist alprenolol

Seven healthy volunteers showing a fourteenfold range in steady-state plasma concentrations on oral alprenolol (200 mg b.i.d.) were investigated by administration of 5 mg of the drug intravenously and then 50, 100, 150, and 200 mg as single oral doses. The rank order for individual steady-state plasma concentrations was the same as that for the relative bioavailability of the 200 mg dose. The area under the plasma concentration-time curve showed a nonlinear increase with the dose. As the relative availability was a good predictor of steady state while clearance after intravenous administration was not, it was concluded that differences in first-pass elimination markedly contribute to the interindividual variability in steady state plasma concentrations. After pentobarbital treatment, the area under the plasma concentration curve of the 200 mg dose was decreased to 32% and 59% of the pretreatment values in two subjects, but there was no change in the plasma half-life of alprenolol. This indicates induction of the first-pass extraction of alprenolol in man.This study was supported by the Swedish Medical Research Council (04X-3902, 04P-4933), the funds of the Karolinska Institutet, and the fund of Tore Nilsson. G. A. held a scholarship from the Association of the Swedish Pharmaceutical Industry (LIF).     

Pharmacokinetics of mirtazapine and lithium in healthy male subjects

A substantial proportion of patients diagnosed with depression and treated with antidepressants show no or insufficient response. In such patients, lithium is often added to the antidepressant for augmentation. The present study investigated the possible drug-drug interaction between mirtazapine and lithium in 12 healthy male subjects in a randomized, double-blind, placebo-controlled two-period cross-over design. Subjects meeting the inclusion and exclusion criteria were randomly assigned to one of two groups. After an overnight fast, they received either a single oral dose of 600 mg lithium carbonate (16 meq Li+) for 10 days at 08.00 h and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9 or the same number (n = 4) of placebo capsules and and a single oral dose of 30 mg mirtazapine at 21.00 h on day 9. At pre-defined times, blood samples were drawn for the measurement of mirtazapine plasma concentrations and lithium serum concentrations. In addition, psychometric tests were performed and the safety and tolerability of the drugs were assessed. The results indicate that mirtazapine does not alter the pharmacokinetics of lithium and vice versa. In addition, the combination of mirtazapine and lithium appeared to be safe and well-tolerated. Extensive psychometric testing after the administration of mirtazapine did not reveal any differences on any tests in subjects on lithium and placebo, respectively.     

Effect of orally administered misoprostol and cimetidine on the steady state pharmacokinetics of diazepam and nordiazepam in human volunteers.

The effects of misoprostol and cimetidine on diazepam pharmacokinetics were evaluated in order to determine whether the kinetic variables for diazepam and nordiazepam alone differ with the repeated oral administration of misoprostol and cimetidine to healthy adult volunteers. The trial was conducted as an open crossover study in 12 normal subjects, divided into two groups with all subjects receiving both regimens. Total study duration was 5 weeks. An initial clinical assessment, including blood biochemistry and assessment of subject oxidation status was carried out on study day 1. On this day, subjects began taking diazepam (10 mg) orally for one week, with pharmacokinetic studies performed at day 8, when steady state levels of diazepam were reached. This was followed by one week with active drug, misoprostol to Group I and cimetidine to Group II, with pharmacokinetic studies performed at the end of a 1-week treatment. After a 2-week wash-out period, both groups took for one week, the alternate drug, i.e. cimetidine plus diazepam to Group I and misoprostol plus diazepam to Group II. On days 8, 15 and 36, subjects were admitted to the hospital for 12 h, during which time a clinical examination was carried out and blood samples were taken at time zero and at 4, 8, 12, 24, and 36 h post-dosing for the measurement of serum diazepam and nordiazepam. The main parameters measured and evaluated were diazepam and nordiazepam pharmacokinetics at steady state (days 8, 15 and 36). These were areas under the curve in the dose intervals (AUC0-24h), maximum plasma concentrations (Cmax), time to peak concentrations (Tmax), elimination half-life (t1/2), elimination constant (Kel), distribution volume (Vd), total body clearance (ClB) and clearance after oral administration (Cloral). The results demonstrated that plasma diazepam and nordiazepam concentrations had a significant increase after steady states have been reached with the simultaneous administration of 800 mg of cimetidine daily for one week. The simultaneous administration of 800 micrograms of misoprostol did not cause any significant change in diazepam and nordiazepam plasma levels after steady states had been reached. Comparing the pharmacokinetic parameters of Groups A and B as well as within groups on days 8, 15 and 36, a significant increase in plasma diazepam and nordiazepam levels was detected. This was due to a cimetidine-induced impairment in microsomal oxidation of diazepam and nordiazepam, which caused a decrease in total metabolic clearance and increased mean steady state plasma concentrations. A more prolonged half-life was observed for both groups taking cimetidine as well as an increase of mean maximum plasma concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)     

A computerised sampling strategy for therapeutic drug monitoring of lithium provides precise estimates and significantly reduces dose-finding time

Abstract: The clinical benefit of implementing Bayesian approach for lithium drug monitoring was evaluated. Intervention group (N = 42) and historical control group (N = 55) patients were each divided into two groups: Dosage with immediate‐release lithium carbonate or a sustained‐release formulation, lithium citrate. Bayesian approach was performed in the intervention groups, and estimation of lithium steady‐state trough concentration was obtained from non‐steady‐state blood sample, collected about 12 hr after the first lithium study dose. The estimate was compared with the actually measured steady‐state concentration. In the control group, lithium monitoring was traditionally performed as steady‐state blood sampling. Predicted and measured lithium concentrations were comparable. The desired lithium dose was reached significantly faster in the intervention group compared to control; 2.47 ± 2.22 days versus 9.96 ± 11.24 days (mean ± S.D.) (p = 0.0003). Bayesian approach was an advantage for the clinicians as a fast and safe aid to obtain the optimal lithium treatment dose.     

Effect of antacid on the bioavailabiity of lithium carbonate

The effect of an antacid on the bioavailability of lithium carbonate was determined in six healthy men in a crossover study. The volunteers were given single 300-mg doses of lithium carbonate alone and with 30 ml of an antacid containing aluminum and magnesium hydroxides with simethicone. Blood samples were collected at various times for 0-24 hours after each dose. The plasma samples were analyzed for lithium using a spectrophotometer, and bioavailability variables were calculated from plasma lithium concentration-time curves. There were no significant differences in peak plasma lithium concentration, time to peak concentration, area under the concentration-time curve from 0 to 24 hours, first-order absorption rate constant, and first-order elimination rate constant between the two treatments. Concurrent administration of antacids and lithium carbonate should not affect lithium blood concentrations.     

Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin.

Twelve subjects received a single oral dose (300 mg) of gabapentin and serial blood and urine samples were collected for drug measurements. Oral phenobarbitone (30-90 mg/day) was then administered to steady-state, and the gabapentin single dose study was repeated on day 42. Gabapentin was administered from days 49 to 52 to achieved steady-state, and further blood and urine samples were collected for drug measurements. Trough plasma phenobarbitone concentrations were monitored at frequent intervals. No statistically significant differences were observed in gabapentin Cmax, tmax, AUC, t1/2 or urinary drug recovery following single doses of gabapentin alone or combined with phenobarbitone. Phenobarbitone did not alter the disposition of gabapentin at steady state. Mean trough steady-state phenobarbitone concentrations were not significantly affected by concomitant gabapentin administration.     

The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling agent, following oral administration to healthy subjects.

1. Tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid) interacts stoichiometrically with haemoglobin to increase oxygen affinity. By decreasing the proportion of insoluble deoxy sickle haemoglobin at capillary oxygen concentrations, tucaresol may be of therapeutic benefit in sickle cell anaemia. 2. In this study, which involved the first administration to man, the pharmacokinetics and pharmacodynamics of tucaresol were studied in healthy male volunteers following oral doses of 200-3600 mg. 3. Peak drug concentrations in plasma and erythrocytes were linearly related to dose; mean (s.d.) values were 95.8 (26.1) and 1035 (67) micrograms ml-1, respectively, at the highest dose. Median tmax in plasma was 6.5 h and in erythrocytes 24.5 h, when approximately 60% of the administered dose was in the target tissue. Plasma drug concentrations fell biexponentially with commencement of the apparent terminal elimination phase at approximately 24 h. The terminal elimination half-life from plasma increased with dose (r = 0.77; P < 0.0001) from 133-190 h at 400 mg to a mean (s.d.) of 289 (30) h at 3600 mg. Erythrocyte drug concentrations declined mono-exponentially with a half-life that was always shorter than the apparent terminal half-life in plasma: overall mean (95% CI) of t1/2 erythrocyte/t1/2 plasma ratio was 0.57 (0.53, 0.61). The erythrocyte AUC/plasma AUC ratio increased with dose (r = 0.67; P < 0.001). 4. The proportion of haemoglobin modified to a form with high oxygen affinity (%MOD) increased in a dose-related manner above doses of 800 mg reaching 19-26% after the 3600 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females.

The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.     

Pharmacokinetics of fosfluconazole and fluconazole following multiple intravenous administration of fosfluconazole in healthy male volunteers

AIMS: To assess the bioavailability of fluconazole (FLCZ) from phosphate pro-drug (fosfluconazole), to investigate the effect of loading doses on the time to achieve FLCZ steady state plasma concentrations and on safety, and to investigate the pharmacokinetics of fosfluconazole following once daily multiple bolus injection of fosfluconazole in healthy male volunteers. METHODS: The first study was a randomized, double-blind, double dummy, two-period crossover study. Subject received either 1000 mg fosfluconazole or 800 mg FLCZ once daily for 14 days in random order. The second study was an open label, randomized parallel group study. Subjects received one of three fosfluconazole once daily treatments: 500 mg for 10 days (no loading dose), a loading dose of 1000 mg on day 1 followed by 500 mg for 9 days (one loading dose), or loading doses of 1000 mg on days 1 and 2 followed by 500 mg for 8 days (two loading doses). RESULTS: The estimated mean (90% CI) bioavailability of FLCZ from fosfluconazole was 96.8% (94.5, 99.2), with a C(max,ss) ratio of 98.3% (93.3, 103.5) in the first study. Less than 1% of the administered dose of fosfluconazole was excreted unchanged in the urine and the majority (85.6%) was eliminated in the urine as FLCZ. In the second study two loading doses regimen led to earlier achievement of target steady state plasma concentrations (by day 3) compared with use of one or no loading dose (towards the end of the dosing period). Similar adverse event profiles were seen in all three treatment groups. Fosfluconazole did not accumulate after multiple dosing. CONCLUSIONS: Multiple administration of 1000 mg fosfluconazole and 800 mg FLCZ produced equivalent systemic exposure to FLCZ. Steady state FLCZ plasma concentrations were achieved earliest when two loading doses were used.     

A double-blind, placebo-controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers

AIMS: The objective of this study was to evaluate the tolerability of a novel dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK). METHODS: In this randomized, placebo-controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double-blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once. RESULTS: Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses > or = 100-200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200-800 mg dose range, Z13752A produced a 50-100% increase of plasma cGMP levels and a 50-80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose-independent. CONCLUSIONS: Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A.     

Absolute bioavailability of chlorthalidone in man: A cross-over study after intravenous and oral administration

Summary Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t_1/2 after i.v. dosing was 36.5 h (±10.5 SD), and the mean plasma t_1/2 after oral doses was 44.1 h (±9.6 SD). The mean red blood cell concentration t_1/2 after i.v. doses was 46.4 h (±9.9 SD), and the mean red blood cell t_1/2 after the oral doses was 52.7 h (±9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (±8.6 SD) % of the intravenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (±8.5 SD) %. Faecal excretion ranged from 1.3–8.5% of dose in the i.v. study to 17.5–31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were — a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F=0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.     

Ascending multiple-dose pharmacokinetics of viramidine, a prodrug of ribavirin, in adult subjects with compensated hepatitis C infection

The current study was carried out to evaluate pharmacokinetic profiles of viramidine and ribavirin in patients (n = 8 per dose group) with compensated hepatitis C infection following oral dosing of viramidine (400, 600, or 800 mg bid for 4 weeks). Pharmacokinetic parameters were determined on days 1 and 29 based on plasma, red blood cell, and urine concentrations of viramidine and ribavirin. The results indicate rapid absorption and conversion of viramidine to ribavirin after oral administration of viramidine. Viramidine and ribavirin exposure in plasma and RBCs generally increased from the 400- to 600-mg dose level of viramidine. However, no further increase in exposure was noted at the 800-mg dose. Long half-lives for viramidine (66-76 hours in plasma and 200-420 hours in red blood cells) and ribavirin (340-410 hours in plasma and 360-430 hours in red blood cells) were noted. A negligible amount of viramidine (1%-4% of dose) and a small amount of ribavirin (9%-14% of dose) were excreted in the urine. The renal clearance was low for both viramidine (5-8 L/h) and ribavirin (4-7 L/h). Significant accumulation of viramidine was noted in red blood cells (accumulation factor [R] = 5-8) but not in plasma (R = 2). Extensive accumulation of ribavirin was noted in both plasma (R = 9-17) and red blood cells (R = 77-129). Steady-state levels of ribavirin and viramidine in plasma and red blood cells were achieved by day 22. At steady state, there was extensive conversion of viramidine to ribavirin in both plasma and red blood cells. Both viramidine and ribavirin were preferentially distributed into red blood cells than plasma.     

Bioavailability of ambroxol sustained release preparations. Part II: Single and multiple oral dose studies in man

The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels.     

A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained-release product

Aims The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration ( C _max ) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.
Methods Limited sampling models (LSM) were developed for CBZ and CBZE following 200–800  mg single oral dose and 400–800  mg twice daily dose for 14 days of a sustained-release product (CBZ-SR) to estimate AUC and C _max. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48  h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state C _min (plasma concentration obtained 5  min before the last CBZ-SR dose).
Results The model provided good estimates of AUC and C _max for CBZ and CBZE. The bias and the precision of the predicted AUC and C _max for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.
Conclusions The method described here may be used to estimate AUC and C _max for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.     

The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily.

Intravenous administration of amlodipine (single dose, 10 mg) to 12 volunteers gave a mean plasma half-life of 34 h, mean clearance of 7 ml min-1 kg-1 and a mean apparent volume of distribution of 21 l kg-1. Oral administration (single dose, 10 mg) to the same 12 volunteers gave a mean systemic availability of 64% and a mean plasma half-life of 36 h. In a second study, repeated oral administration (once daily for 14 days, 15 mg) to 28 volunteers resulted in steady state plasma drug concentration being reached after seven doses, an accumulation of approximately threefold and a mean half-life of 45 h.