Pharmacokinetic/pharmacodynamic modelling of effects of dexamethasone and prednisolone in combination with endogenous cortisol on lymphocyte counts and systemic markers of bone turn over and inflammation in healthy and asthmatic men.

OBJECTIVE: To compare potency and efficacy of dexamethasone (DEXA) and prednisolone (PRED) in assumed equipotent doses in combination with endogenous cortisol, using lymphocyte counts, plasma osteocalcin (OC), and eosinophilic cationic protein (ECP) as effect variables and to evaluate potential differences between healthy subjects and asthmatic patients. METHODS: Eight healthy subjects and six asthmatic patients who had stopped taking their regular inhaled glucocorticosteroid treatment (ICS) for 1 week, were given an IV bolus of DEXA and PRED in assumed equipotent doses of 2.0 mg and 12.5 mg, respectively, on separate occasions, in combination with subcutaneously injected granulocyte-colony-stimulating factor (G-CSF) as a stimulant for ECP production. Plasma levels of DEXA, PRED, cortisol and effect variables were determined over 25 h and pharmacokinetic-pharmacodynamic (PK-PD) modelling was performed. RESULTS: Baseline cortisol concentration was lower in patients than in healthy subjects. Both of the exogenous glucocorticoids (GCs) diminished cortisol production. In the healthy subjects, the cortisol production remained suppressed for the full duration of the study day after DEXA but not after PRED. In the asthmatic patients though, the reappearance of the endogenous production of cortisol was seen after both DEXA and PRED. The E(max) values for lymphocyte counts and OC showed that cortisol acted as partial, and DEXA and PRED as full agonists. The observed responses of DEXA and PRED suppressing cortisol, OC and lymphocyte counts were all of the same relative order of magnitude, in accordance with the estimated PD parameters. However, cortisol was estimated to have very little effect on ECP and modelling further predicted that DEXA and PRED were only partial agonists for this effect, without a difference between healthy and asthmatic subjects. Yet, in healthy subjects, the area under the concentration-time curves (AUCs) indicated unexpectedly that ECP was only suppressed after PRED and not after DEXA, while in patients it was suppressed after both GCs. The rank order of potency on lymphocyte counts, OC and ECP was DEXA>PRED>cortisol, although the different relative potencies of the three GCs involved were not the same for all of the three effect variables and differences were also found between healthy and asthmatic subjects. CONCLUSION: PK-PD modelling studies of GCs demonstrated not only differences in potency of DEXA and PRED on the measured systemic markers, but also different potencies per target tissue and differences between healthy and asthmatic men. The effects caused by the achieved blood concentrations of DEXA and PRED, expressed as AUCs of the effect variables, were in accordance with their respective E(max) values in case of the lymphocytes and OC but not for ECP.

Distinct actions of prednisolone and dexamethasone towards osteocalcin and eosinophilic cationic protein in assumed clinically equivalent doses: a study in healthy men.

OBJECTIVE: To study the effects of prednisolone (PRED) and dexamethasone (DEXA) in assumed clinically equivalent doses towards the lowering of cortisol, osteocalcin (OC) and the stimulated rise of eosinophilic cationic protein (ECP) by granulocyte colony stimulating factor (G-CSF). METHODS: At four separate sessions of 25 h each, saline i.v. alone, G-CSF s.c. alone or in combination with either 12.5 mg PRED i.v. or 2.0 mg DEXA i.v., were randomly administered in eight healthy male subjects. RESULTS: All subjects had equal lowering of cortisol after DEXA and PRED at 10 h, whereas a sustained suppression at 25 h persisted only after administration of DEXA. Between 4 h and 10 h after administration of DEXA and PRED, the change in the area under the concentration-time curve (DeltaAUC4-10) of OC became 24.4% and 2.3% lower, respectively ( p<0.0001). After 25 h, this effect persisted for DEXA. DeltaAUC4-10 of the G-CSF-stimulated ECP response decreased by a mean of 76.8% after PRED compared with DEXA and to controls ( p<0.02), and this difference had disappeared at 25 h. DEXA did not elicit any effect towards the G-CSF-stimulated ECP response. CONCLUSION: PRED and DEXA in formerly assumed clinically equivalent doses induced a similar suppression towards cortisol within the first 10 h, but had different actions towards blood concentrations of OC and ECP following G-CSF stimulation in healthy male subjects.

Lack of relationships between cumulative methylprednisolone dose and bone mineral density in healthy men and postmenopausal women with chronic low back pain.

The medical use of glucocorticoids (GCs) is related to low bone mineral density (BMD). In this study we tested the hypothesis that the cumulative dose of GC is not related to BMD outcome. The study was cross-sectional in design and included healthy individuals with chronic low back pain resistant to conventional treatments. In two steroid-naive subjects cortisol and methylprednisolone (MP) concentrations were serially assessed after a single MP depot injection (160 mg epidurally). Furthermore, in 14 men and 14 postmenopausal women, previously treated with multiple epidural MP depots, endocrine parameters were analysed in relation to BMD outcomes. The minimal cumulative MP dose received by all 28 subjects was 3 g. In the two steroid-naive subjects, cortisol concentrations were completely suppressed for at least 6 days and partly recovered over the course of 30 days. During this period, MP concentrations remained detectable in plasma. In the 28 subjects, the cumulative MP dose received was 7.76+/-4.23 g in the men and 8.50+/-3.13 g in the women (mean+/-1SD). None of the men had osteoporosis, but osteopenia was prevalent in 78.5% according to WHO criteria extrapolated to men. Half of the women had osteoporosis and half of them had osteopenia. The body mass index (BMI) and endogenous oestradiol levels of the men were not related to BMD outcomes. Univariate linear relationships in women were found between BMI and spinal ( r 0.62; P=0.02) and total hip BMD ( r 0.61; P=0.03), but not femoral neck BMD. In women, relationships were also found between the total and, for protein binding-corrected oestradiol levels, and spinal BMD ( r 0.70; P=0.01 and r 0.72; P=0.01, respectively) and total hip BMD ( r 0.53; P=0.08 and r 0.56; P=0.05, respectively). No significance was observed between endogenous oestradiol levels and the BMD of the femoral neck. The administration of a single MP depot injection (160 mg) resembled a systemic low peak dose GC exposure. The administration of multiple MP depots in men and women with chronic low back pain revealed no relationship between cumulative GC dose and BMD. These findings support the hypothesis of a non-existent relationship between cumulative GC dose and BMD outcomes in healthy men and women with a prior GC administration of at least 3 g.

Pharmacokinetics of a single oral dose of baclofen in pediatric patients with gastroesophageal reflux disease.

Transient relaxation of the lower esophageal sphincter (TLESR) is the predominant mechanism of gastroesophageal reflux (GER) in adults and children. Baclofen [4-amino-3-(p-chlorophenyl)-butanoic acid], a gamma-aminobutyric acid (GABA)-B receptor agonist used for the management of spasticity, has been recently shown to significantly inhibit GER in healthy adults without any relevant side effects. The objective of this study was to evaluate the pharmacokinetics of baclofen in a pediatric population with GER disease. In an open-label single-dose pharmacokinetic study, eight children with the diagnosis of GER made on clinical grounds received an oral dose of baclofen, 2.5 mg. Blood samples were drawn from an indwelling venous catheter, and urine was collected during a postdose period of 8 hours. The concentration of baclofen in these body fluids was determined using a validated high-performance liquid chromatography (HPLC) method with electrochemical detection after OPA-sulfite derivatization. Pharmacokinetic data were analyzed using the nonlinear regression program Scientist. Serum concentration-time curves could be best described using a two-compartment open model with a lag time. Mean plasma clearance (Cl) was 315.9 mL/h/kg; volume of distribution (Vd) was 2.58 L/kg; and half-life (T(1/2)beta) was 5.10 hours. No side effects were noted. As half-lives were comparable with those found in adult studies, the risk for accumulation seems not greater in children than in adults. Body composition can have a strong influence on the Vd of baclofen and, therefore, on the dose needed to obtain therapeutic plasma levels. Dosing according to clearly defined age groups with the help of therapeutic drug monitoring seems preferable. In view of the negative correlation between body weight and Vd, dosing according to body weight using adult pharmacokinetic data does not seem an effective way for using baclofen in children.

Effect of grapefruit juice or cimetidine coadministration on albendazole bioavailability.

The assumed metabolic breakdown of albendazole by mucosal CYP3A4 enzymes was studied by coadministering albendazole (10 mg/kg) with grapefruit juice. Concentrations of albendazole sulfoxide (ABZSX), the active metabolite of albendazole, were compared with those after albendazole was administered with water, a fatty meal, or grapefruit juice plus cimetidine (10 mg/kg). In comparison to water, maximum ABZSX concentration (Cmax) was enhanced 6.5-fold by a fatty meal (from 0.24 +/- 0.09 mg/l to 1.55 +/- 0.30 mg/l; mean +/- SD; P < 0.001) and 3.2-fold by grapefruit juice (from 0.24 +/- 0.09 mg/l to 0.76 +/- 0.37 mg/L; P = 0.031). When grapefruit juice was combined with cimetidine, Cmax was significantly lower than with grapefruit juice alone (0.41 +/- 0.29 mg/l and 0.76 +/- 0.37 mg/l, respectively; P = 0.022). The area under the concentration-time curve from 0 to infinity (AUC(0-omega)) followed a comparable pattern. Half-life (T(1/2)) was 8.8 +/- 4.2 hr and 8.2 +/- 4.3 hr after administration with water or a fatty meal (P = 1.000). Grapefruit juice shortened T(1/2) by 46% (P = 0.026). We hypothesize that albendazole is metabolized by CYP3A4 enzymes in the intestinal mucosa. This process can be inhibited by grapefruit juice. Cimetidine decreased albendazole bioavailability.

Beat-to-Beat Measurement of Cardiovascular Effects of a Single Subcutaneous Dose of Terbutaline in Healthy Subjects.

OBJECTIVE: To evaluate the cardiovascular effects over time of a single subcutaneous (SC) dose of terbutaline 0.75mg in young healthy volunteers using continuous, beat-to-beat monitoring of cardiovascular effects. DESIGN AND METHODS: Nine healthy young volunteers were administered a SC dose of terbutaline sulphate 0.75mg. Cardiovascular effects were continuously monitored over 2 hours using Finapres and Modelflow technology. Blood was drawn at several timepoints for determination of the plasma terbutaline concentration. RESULTS: The peak plasma concentration of terbutaline was 17.3 ± 4.5 (µg/L at 28.9 ± 12.5 minutes after SC administration. Changes in cardiovascular parameters were observed very quickly, with increases in stroke volume (16.7 ±8.9%), cardiac output (46.0 ± 22.6%), systolic blood pressure (15.1 ± 11.6%) and heart rate (48.1 ± 15.7%) at 9.3 ± 3.8, 16.9 ± 4.8, 21.3 ± 8.9 and 49.7 ± 16.4 minutes, respectively. In five of eight subjects a very rapid (at 9.6 ± 3.7 minutes) drop in diastolic blood pressure (9.8 ± 5.1 %) was observed, while total peripheral resistance decreased maximally by 33.5 ± 7.9% at 18.9 ± 7.1 minutes. CONCLUSIONS: The magnitude of the cardiovascular effects again stresses the need for cautious use of SC terbutaline in patients with a history of cardiovascular disease. The time-course of some of the cardiovascular effects of a SC dose of terbutaline in relation to terbutaline plasma concentrations was unexpected and suggests direct ß2-adrenoreceptor-mediated effects on the heart. Further investigations using both selective and nonselective ß-receptor antagonists are needed to unravel the complex interactions of ß2-receptor-mediated terbutaline-induced effects and cardiovascular reflex mechanisms.

Prevention by theophylline of beta-2-receptor down regulation in healthy subjects.

Adrenergic down-regulation can occur rapidly in many tissues. Therefore beta 2-agonists might have a rapidly decreasing effect in time, which is a potential problem for the treatment of bronchial asthma. This in vivo study tested the hypothesis that theophyline can prevent adrenergic down-regulation. A randomised, double blind, placebo-controlled cross-over study was performed in eight healthy subjects. Terbutaline concentration-effect relationships were studied before and after one week of dosing of terbutaline, with or without theophylline. Slow-release terbutaline 5 mg daily was administered for 7 days in combination with either placebo or slow-release theophylline. Concentration-effect relationships of terbutaline after a single subcutaneous injection were studied before and after the 7 day terbutaline treatment. Eosinopenia and hypokalemia were the systemic effect parameters. Terbutaline concentration-time courses were described with a two-compartment model and those of theophylline with a polynomial equation. A hypothetical effect compartment model was applied to link terbutaline plasma concentration via an Emax model to the studied effects. The interaction of theophylline and terbutaline was described with a non-competitive pharmacodynamic model. After one week of oral terbutaline, the mean EC50 (ng/L) of terbutaline increased for the eosinopenia from 1.87 +/- 1.66 to 3.78 +/- 2.18 (+102%) (p = 0.012) with placebo, and to 2.73 +/- 1.99 (+46%) (p = 0.025) with theophylline; for the hypokalemia the EC50 increased from 4.70 +/- 2.91 to 8.52 +/- 7.26 (+81%) (p = 0.012) with placebo, and to 5.64 + 2.59 (+20%) (p = 0.16) with theophylline. The results indicate that the non-specific phosphodiesterase inhibitor theophylline can prevent terbutaline-induced adrenergic down-regulation to a substantial degree.

Effect of dose increase or cimetidine co-administration on albendazole bioavailability.

The low bioavailability of albendazole affects the therapeutic response in patients with echinococcosis. Cimetidine co-administration is reported to improve bioavailability. To analyze the assumed dose-dependent bioavailability of albendazole, we administered 5 to 30 mg/kg albendazole to 6 male volunteers in a randomized cross-over study. To assess the effect of cimetidine (10 mg/kg twice daily), the drug was given with albendazole (20 mg/kg). A dose-dependent bioavailability was not observed. This was due to inter-individual variability of the maximal concentration (Cmax 38%-72%) of albendazole sulphoxide (ABZSX), the active metabolite of albendazole. Cmax was 0.21+/-0.14 mg/L after 5 mg/kg and 0.39+/-0.19 mg/L after 30 mg/kg albendazole (P = 0.217). Cimetidine tended to decrease Cmax by 52% (P = 0.109) and significantly inhibited ABZSX breakdown as indicated by the prolongation of ABZSX elimination half-life from 7.4+/-3.3 hr to 19.0+/-11.7 hr (P = 0.028). Remarkably, the inter-individual variability of Cmax was significantly lower during cimetidine co-administration: 14% versus 72%.

The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects.

BACKGROUND: Artemether is a new and effective treatment for malaria, although relapse is a problem in monotherapy. These relapses could be related to a time-dependent decline in artemether plasma levels described in multiple-dose studies and probably caused by autoinduction. The aim of this study was to evaluate the effect of grapefruit juice on the decreasing bioavailability over time of artemether. METHODS: In a randomized, two-phase crossover study, eight healthy male subjects took 100 mg oral artemether with 350 mL water or with 350 mL double-strength fresh frozen grapefruit juice once daily for 5 days. On day 1 and day 5, 17 blood samples were collected over a period of 8 hours. RESULTS: The mean peak artemether plasma concentration (Cmax) and the mean area under the concentration-time curve (AUC) after the last dose at day 5 were about one third compared with day 1, without a change in the elimination half-life after intake with water (P = .006 for Cmax; P = .005 for AUC) and with grapefruit juice (P < .001 for Cmax and AUC). Grapefruit juice increased Cmax (P = .021) and AUC (P < .001) twofold on day 1 (P = .021) and day 5 (P = .05 for Cmax; P = .004 for AUC). Dihydroartemisinin, the active metabolite, showed a twofold increase in Cmax (P = .006) and AUC (P = .001) with grapefruit juice, without time-dependent changes of pharmacokinetic parameters. CONCLUSIONS: Grapefruit juice significantly increased the oral bioavailability of artemether but did not prevent the time-dependent reduction in bioavailability. It suggests that CYP3A4 in the gut wall is one of the metabolizing enzymes of artemether but seems to not be involved in the autoinduction process.

The development of an immunoassay for the detection of artemisinin compounds in urine.

We have produced monoclonal antibodies against artelinic acid and investigated the reactivity with artemisinin drugs and metabolites. Antibody F170-10 is fairly specific for artelinic acid but does bind artemisinin and artemether (3-5% cross-reactivity). Dihydroartemisinin, artesunate, and metabolites of artemisinin showed less reactivity. With this antibody, an inhibition ELISA has been set up to detect artemisinin compounds in urine. In healthy subjects who received a single oral dose of artemisinin, artemether, artesunate or dihydroartemisinin, ELISA reactivity in urine was found. This reactivity in urine paralleled the plasma concentrations of artemether and dihydroartemisinin. The results show that this immunoassay for artelinic acid can be used to detect artemisinin compounds in urine for about 8 hr after intake. With a more sensitive test, this simple method as a urine dipstick may be become useful for drug use and compliance studies in malaria-endemic areas where the artemisinin derivatives are increasingly used.

Grapefruit juice increases the bioavailability of artemether.

OBJECTIVE: To evaluate the effect of grapefruit juice on the pharmacokinetics of artemether in plasma and saliva after a single oral dose and to detect concentration-dependent electrocardiographic changes (bradycardia and QTc prolongation). METHODS: Six healthy male subjects were given a standard breakfast followed by two tablets of 50-mg artemether administered with water; 1 week later, the tablets were administered with 350 ml double-strength fresh frozen grapefruit juice. For 8 h, 17 blood- and saliva samples were collected, and 17 electrocardiograms were recorded. Drug and metabolite concentrations were measured by means of high-performance liquid chromatography with electrochemical detection. The pharmacokinetic parameters were determined using a one-compartment model. RESULTS: Grapefruit juice significantly (P = 0.001) increased the mean peak concentration (Cmax) of artemether more then twofold from 42 (SD 17) ng/ml to 107 (28) ng/ml. The time to reach Cmax (tmax) with grapefruit juice was 2.1 (0.6) h compared with 3.6 (17) h with water (P = 0.02). The area under the concentration time curve (AUC) almost doubled with grapefruit juice from 177 ng x h/ml to 336 ng x h/ml (P = 0.003). The elimination half-life remained unchanged (1.0 h vs 1.3 h). No major changes in the kinetics of the metabolite dihydroartemisinin were detected. Low artemether levels and zero dihydroartemisinin levels were found in saliva. No influences of artemether were observed on 17 electrocardiograms during the 8 h after drug intake in particular there were no signs of bradycardia or QTc prolongation. CONCLUSION: Grapefruit juice significantly increases the oral bioavailability of artemether without an effect on the elimination half-life. It suggests a role for intestinal CYP3A4 in the presystemic metabolism of artemether.

Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria.

Multiple dose pharmacokinetics of artemether and dihydroartemisinin were investigated in chinese patients treated for malaria. They received over 2 days either 4 x 80 mg artemether orally (n = 48) or 4 x 80-480 mg co-artemether (n = 40), a combination of artemether and lumefantrine (benflumetol). Lag time = 0.48 h (mean), Cmax after first dose = 157 ng/ml, t(max) = 1.73 h and elimination half-life = 1.16 h. The lag and absorption times were 0.5 h longer for co-artemether compared with artemether. Dihydroartemisinin paralleled artemether pharmacokinetics. Artemether Cmax after the last dose was one-third of the Cmax after the first dose while, inversely, dihydroartemisinin Cmax increased over time. We suggest that auto-induction of gut mucosa enzymes and/or liver enzymes causes a time-dependent increase in first-pass metabolisation of artemether.

Pharmacokinetic/pharmacodynamic modelling of the eosinopenic and hypokalemic effects of formoterol and theophylline combination in healthy men.

Interactions of formoterol and theophylline were evaluated with the use of pharmacokinetic-pharmacodynamic (PK/PD) modelling. Oral doses of 144 microg of formoterol and 375 mg of theophylline were given separately or combined to healthy subjects. As effect parameters, plasma eosinophil and potassium concentrations were used. Kinetic interactions between formoterol and theophylline were not found. Plasma drug concentrations were linked to the observed effects via an effect compartment model with a sigmoid E max model. The E max values+/-SD for the hypokalemic effects were 2.29+/-0.78 mmol/l for formoterol and 1.64+/-1.16 mmol/l for theophylline (P>0.05). The E max values for the eosinopenic effects were fixed at zero. The EC 50 values of the eosinopenic and hypokalemic effects were respectively 91.4+/-38.2 pg/ml and 128.4+/-52.9 pg/ml for formoterol, and 11. 9+/-4.6 microg/ml and 15.5+/-4.8 microg/ml for theophylline. Effects of both drugs combined were described with a non-competitive interaction model. The correlation coefficients of the fits of the eosinopenic and hypokalemic effects were respectively 0.9520+/-0. 0311 and 0.9371+/-0.0227, supporting our hypothesis of non-competitive interaction.

Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication.

Registration in Europe of several artemisinin drugs for the treatment of malaria can soon be expected. Artemisinin is isolated from the herb Artemisia annua, in use in China more than 2000 years as a herbal tea against fever. Artemisinin drugs are being used extensively in South-East Asia and increasingly in Africa. Active derivatives have been synthesized - artemether, arteether and artesunate - which are used for oral, intramuscular, rectal and intravenous administration. The origin, mechanism of action, efficacy and safety in patients, the pharmacokinetics and the position of this group of compounds among existing antimalarials are discussed in this review.

Simultaneous determination of fentanyl and midazolam using high-performance liquid chromatography with ultraviolet detection.

When measuring fentanyl and midazolam simultaneously in the same plasma sample with standard high-performance liquid chromatography-ultraviolet (HPLC-UV) detection, overlap of the fentanyl peak by the midazolam peak occurs, which makes fentanyl determination impossible. We tested the hypothesis that by acidifying the methanol mobile phase with 0.02% perchloric acid, 70%, it would be possible to separate both peaks. The UV detector was set at 200 nm. Calibration curves for fentanyl (range 0-2000 pg/ml) and midazolam (range 0-400 ng/ml) were linear (r>0.99). The detection limits were 200 pg/ml (fentanyl) and 10 ng/ml (midazolam). Precision and accuracy for intra- and inter-assay variability as well as in-line validation with quality control samples (QCS) were acceptable (<15 and 20%, respectively), except for fentanyl QCS of 200 pg/ml (17.8% precision). Although less sensitive than gas chromatography-mass spectrometry (GC-MS), reliable measurements of fentanyl, simultaneously with midazolam, can be performed with this HPLC-UV system.

The pharmacokinetics of artemisinin after administration of two different suppositories to healthy Vietnamese subjects.

Eight healthy Vietnamese male subjects received 400 mg artemisinin formulated into fatty suppositories (FS), and six different subjects received 500 mg of artemisinin formulated in polyethylene glycol suppositories (PEGS). Plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection; concentration versus time curves were analyzed with nonparametric methods. No statistically significant differences were found between the two formulations. The maximum concentration (Cmax) was 100 +/- 102 microg/L (mean +/- SD, range = 24-330) microg/L (FS), the pharmacokinetic lag time (Tlag) was 1.3 +/- 1.0 hr (range = 0-3) (FS), and the time of the maximum concentration (Tmax) was 7.1 +/- 2.1 hr (range = 3-10) hr (FS). Because artemisinin is not available for intravenous dosage, absolute bioavailability cannot be assessed. However, compared with a previous study on oral artemisinin in healthy Vietnamese subjects, bioavailability relative to oral administration was estimated to be approximately 30%. We conclude that therapeutic blood concentrations of artemisinin can be reached after rectal dosage. The dose after rectal administration should probably be higher than after oral administration; doubling or tripling the oral dose might be necessary, which would imply a rectal dose of at least 20 mg/kg of body weight given twice a day.

Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for Falciparum malaria.

Six patients with uncomplicated falciparum malaria received artesunate for 5 days. Plasma concentrations of artesunate and dihydroartemisinin were determined by high-performance liquid chromatography with electrochemical detection. The concentrations of dihydroartemisinin in plasma 2 h after a dose showed a time-dependent decline. Concentrations of artesunate in plasma especially after the last dose, were very low. Despite this, all patients responded with a fast recovery.

The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects.

The contribution of the enzymes CYP2D6 and CYP2C19 to the metabolism of artemether was evaluated in a cross-over study in seven healthy adult Caucasian subjects. The pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin were compared when given 100 mg artemether orally alone or in combination with either CYP2D6-inhibitor quinidine or CYP2C19-inhibitor omeprazole. Plasma concentrations of artemether and dihydroartemisinin were measured with reversed phase high performance liquid chromatography with electro-chemical detection (HPLC-ED). Artemether was rapidly absorbed with a mean tmax of 0.8 h (95% confidence interval, CI=0.5-1.1) reaching a mean Cmax of 29 ng/ml (14-45 ng/ml). The mean elimination half-life was 1.3 h (0.8-1.8 h). The pharmacokinetic parameters for dihydroartemisinin were not significantly different from those for artemether. Artemether combined with quinidine revealed no significant changes in the plasma concentrations of either artemether or dihydroartemisinin. No changes were seen in the combination with omeprazole as a CYP2C19 inhibitor. A second peak in the plasma concentration profile was observed 2-4 h after drug intake. This phenomenon was possibly related to variable gastric emptying. No major contribution of the enzymes CYP2D6 or CYP2C19 was found in artemether metabolism. No interethnic differences in artemether metabolism on the basis of a genetic polymorphism of these enzymes is to be expected.

The pharmacokinetics of artemisinin suppositories in Vietnamese patients with malaria.

Eight male Vietnamese malaria patients received 600 mg of artemisinin in a single dose of 3 suppositories containing 200 mg each; 24 h later they received a single oral dose of mefloquine, 15 mg/kg. Plasma artemisinin concentrations were measured until 24 h after dosing, and parasites were counted until none could be detected. Artemisinin concentration versus time curves of all subjects were analysed with model-independent methods. Mean Cmax was 108 micrograms/L (SD = 60, range 29-169), mean tlag was 0.3 h (SD = 0), mean tmax was 6.5 h (SD = 3.9, range 2-14). By comparing the area under the concentration-time curve with that found in a previous study on oral artemisinin, average bioavailability relative to oral administration was estimated to be approximately 30%. Median parasite clearance time was 24 h (range 24-72). We concluded that therapeutic blood concentrations of artemisinin can be reached after rectal administration. There was a large inter-individual variation in blood concentrations attained. The dose given by rectal administration should probably be twice the usual oral dose, i.e., at least 20 mg/kg of body weight twice daily.

Pharmacokinetics and effects of formoterol fumarate in healthy human subjects after oral dosing.

OBJECTIVE: To evaluate the effects of formoterol after oral administration on plasma eosinophils and plasma potassium in healthy subjects. METHODS: Plasma concentrations of formoterol, peripheral eosinophil count and plasma potassium were determined during 7 h after oral administration of 168 microg of formoterol to eight healthy subjects. Descriptions of the concentration-time course of formoterol are given using a one-compartment pharmacokinetic model with first-order absorption in four subjects and a two-compartment model in the other four subjects. Effects on potassium and eosinophils are described using pharmacokinetic/pharmacodynamic (PK/PD) modelling with the 'effect-compartment' approach. RESULTS: The values of the kinetic parameters were: Ka: 6.9 (h(-1)), t1/2, 8.5 (h), AUC: 741 (pg x h(-1) x l(-1), V(area/f): 1470 (l). Formoterol concentrations were related to dynamic data using a sigmoid Emax model. CONCLUSION: Plasma concentrations of formoterol can be measured in plasma of healthy subjects after oral administration. These data can be used for describing concentration-effect relations with respect to plasma potassium and eosinophils. With comparable EC50 values for the two effects, remarkable differences were found for k(e0) and n values.