C. J. van Boxtel

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.

Grapefruit juice increases the bioavailability of artemether

AbstractObjective: 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 · h/ml to 336 ng.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.

Comparison of the half-life of antipyrine in plasma, whole blood and saliva of man.

SummaryA previously described GLC method has been modified and applied to measurement of antipyrine levels in plasma, blood and saliva of man following administration of a single oral dose (10 mg/kg). The levels in blood and saliva were comparable to those in plasma at every time studied. The half life of antipyrine determined in blood, plasma or saliva in any given individual was similar. The intersubject variation in half-life was about two-fold (n=5). Antipyrine levels in saliva were not affected by the rate of saliva flow when collections were made continuously for 20 minutes. This study has demonstrated that kinetic data about antipyrine comparable to that from plasma may also be obtained from readily accessible tissue fluids, such as saliva and capillary blood.

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

SummaryThe 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.

Failure of Vitamin C to Affect the Pharmacokinetic Profile of Antipyrine in Man

A possible interaction of vitamin C with the metabolism of drugs which are oxidized (e.g., antipyrine and diphenylhydantion) is indicated from data in animals. The effect of megadoses of vitamin C (300 mg/day to 4800 mg/day) was therefore tested in human volunteers receiving antiprine (single oral dose) or diphenlhydantoin (chronic therapy). The half-life, volume of distribution, and plasma clearance of antipyrine were not affected by vitamin C treatment. Steady-state plasma levels of diphenylhydantoin in two epileptic patients were similar before and during vitamin C (1.2 Gm/day for 18 days) treatment. It is concluded that vitamin C, in commonly used megadoses, has no effect on the metabolism of antipyrine or diphenylhydantoin in men.

The effect of oxprenolol dosage time on its pharmacokinetics and haemodynamic effects during exercise in man.

SummaryWe have studied the effect of dosage time of oxprenolol (Trasicor®) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses.There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P=0.04) and for elimination half-life (P=0.006). Both were lowest after administration at 14.00 h (163 (77) l and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) l, and 1.7 (0.6) h).The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P=0.03).The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and Emax did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.

Hypokalaemia in Healthy Volunteers after Single and Multiple Doses of Formoterol or Salbutamol

SummaryA specific β2-adrenoceptor-mediated effect, hypokalaemia, was studied in healthy volunteers after single as well as multiple dosages of the long-acting agonist formoterol and the short-acting agent salbutamol. The purpose of the study was to test with simple methodologies if rapidly induced tachyphylaxis for this well known systemic effect can be shown and if it will then be more pronounced for the long-acting compound. Hypokalaemia induced by inhalation of, respectively, 72μg formoterol and 1200μg of salbutamol was studied before and after 1 week of medication. Potassium-time curves were described by a biexponential equation and also analysed with a deconvolution technique. Both drugs induced a statistically significant hypokalaemia, the duration of this effect being considerably shorter for salbutamol than for formoterol (p < 0.05 with both methods of analysis). After multiple doses for 1 week, both maximal hypokalaemia and the area under the curve of the hypokalaemic effect had decreased after inhalation of formoterol (p < 0.05) but not after inhalation of salbutamol.It was concluded that plasma potassium as an effect measurement can be used to study in a simple but reproducible way differences of pharmacological interest between various β2-adrenoceptor agonists.

High-dose methotrexate with citrovorum factor rescue in non-small-cell lung cancer

SummaryNineteen patients with non-small-cell carcinoma of the lung were treated with high-dose methotrexate and leucovorin rescue. Two partial responses (10.5%) were observed, lasting 13 and 17 weeks. Toxicity was acceptable. It is concluded that the occasional benefit of high-dose methotrexate with leucovorin rescue at this dose and according to the schedule described for these patients does not warrant further study.

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

ObjectiveTo 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 methodsNine 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.ResultsThe 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.ConclusionsThe 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 β2-adrenoreceptor-mediated effects on the heart. Further investigations using both selective and nonselective β-receptor antagonists are needed to unravel the complex interactions of β2-receptor-mediated terbutaline-induced effects and cardiovascular reflex mechanisms.