Hydroquinine pharmacokinetics after oral administration in adult patients with muscle cramps

Objective: This study was conducted to determine the pharmacokinetic properties of hydroquinine after oral administration in adult patients with muscle cramps. The main reason for this study was the poor availability of pharmacokinetic data, hindering the design of studies to explore the possible relationship between hydroquinine concentrations and effects. Methods: Sixteen adult patients with a clinical history of muscle cramps were given once-daily oral doses of 300 mg hydroquinine hydrobromide for 4 days. Serum and saliva samples were taken following a predefined schedule until 24 h after the last dose. Urine was collected during the study period. Hydroquinine concentrations were measured, and calculations were made of pharmacokinetic parameters using non-linear curve fitting. Results: Pharmacokinetics of hydroquinine could be best described using a one-compartment open model. After oral administration, hydroquinine was rapidly absorbed (mean ± SD: maximum concentration 2.43 ± 0.68 mg/l; time to maximum concentration 1.4 ± 1.2 h; lag time 0.54 ± 0.50 h). With an elimination half-life of 10.9 ± 6.1 h, steady-state was reached in several days. The distribution volume was 1.24 ± 0.29 l/kg, total clearance was 6.7 ± 3.2 l/h. The measured unbound hydroquinine fraction was 8.6 ± 3.0%. No correlation was found between saliva and serum concentrations. Cumulative urinary excretion of unchanged hydroquinine 24 h after the first dose was 35.5 ± 9.2 mg. Conclusion: Pharmacokinetic properties of hydroquinine are roughly similar to those of quinine. The unchanged fraction of hydroquinine excreted in urine is higher than that reported for quinine. Saliva hydroquinine concentrations could not be related to serum values. Steady-state trough or other fixed-time serum concentrations may prove useful for further optimisation of hydroquinine dosage. Received: 19 November 1999 / Accepted: 9 March 2000     

The pharmacokinetics of pravastatin in patients on chronic hemodialysis

Objective: The single-dose and steady-state pharmacokinetics of the HMG CoA reductase inhibitor pravastatin and its two metabolites, SQ 31 906 and SQ 31 945, were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was employed, followed by daily oral dosing of 20 mg over four hemodialysis intervals. Results: No statistical differences in the pharmacokinetics of pravastatin or SQ 31 906 were evident when comparing the first and last days of oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and SQ 31 906 were similar to those of healthy volunteers. SQ 31 945, the inactive polar metabolite, did accumulate in dialysis patients, as evidenced by an accumulation index of 1.7 ± 1.0. Although metabolic clearance is the predominant mode of elimination of pravastatin, hemodialysis clearances of pravastatin, SQ 31 906 and SQ 31 945 will contribute to total body clearance since dialytic clearance ranged from 40 to 80 ml · min⁻¹. Conclusion: Pravastatin can be safely administered in the usual dosages to subjects with renal failure on hemodialysis and no change in dosing is necessary. Received: 7 January 1997 / Accepted in revised form: 12 May 1997     

Effect of intravenous dopamine infusion on plasma concentrations of dopamine and dopamine sulfate in men, during and up to 18 h after infusion

Objective: We investigated whether sulfoconjugation contributes to the inactivation of intravenously infused dopamine (DA) in low concentrations with a predominant action on the kidney. Methods: Plasma DA and dopamine sulfate (DA-S) concentrations were determined during 4 h of intravenous infusion of DA (2 μg/kg/min) and up to 18 h after cessation of infusion. Twenty-seven healthy young subjects participated in the placebo controlled, randomised and double-blind study. Results: Intravenously administered DA was sulfoconjugated rapidly and to a great extent. After starting the infusion, DA levels rose within minutes and reached a steady state after 30–60 min. The steady-state levels averaged 151.3 ± 8.2 nmol/l. DA-S levels also increased markedly with infusion from 16.7 ± 9.9 nmol/l at the start of infusion up to 261.2 ± 24.2 nmol/l at 30 min after cessation of infusion. Plasma DA concentrations after cessation of the infusion decreased rapidly with an initial half-life of elimination of 4.8 min. Concentrations of plasma DA-S declined with a half-life of 4.5 h. Persistent elevations of free and conjugated DA compared with pre-treatment levels were observed even 18 h after cessation. Heart rate and blood pressure remained unchanged both during DA and saline infusion. Conclusion: Findings indicate that the sulfoconjugation pathway contributes markedly to the inactivation of intravenously infused DA and seems not to be saturable by DA infusion in low doses. Received: 8 March 1999 / Accepted in revised form: 21 September 1999     

Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator

Purpose: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. Methods: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25–200 mg. Standard pharmacokinetic parameters were assessed. Results: In the single-dose study, time to reach peak concentration (t_max) ranged from 1.3 h to 4.0 h; peak concentration (C_max) ranged from 15 ng/ml to 445 ng/ml; and the estimated terminal elimination half-life (mean ± SD; t_1/2) was 24.8 ± 7.0 h. In the repeated-dose study, t_max ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. C_max ranged from 295 ng/ml to 1043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t_1/2 at all dose levels was 29.7 ± 1.5 h (overall mean ± SD). Strong linear correlations between the dose and C_max and between the dose and the area under the curve were observed in both studies. Conclusion: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens. Received: 12 July 1999 / Accepted in revised form: 18 May 2000     

Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects

Objective: The pharmacokinetic and pharmacodynamic properties of YM087, (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a new orally active, dual V₁/V₂ receptor antagonist were characterised in healthy normotensive subjects. Methods: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study. Results: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V₂ receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 ± 1.3 mosmol/l to 288 ± 1.0 mosmol/l after i.v. and from 283 ± 2.1 mosmol/l to 289 ± 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 ± 0.3 pg/ml to 3.7 ± 0.6 pg/ml after i.v. and from 0.9 ± 0.1 pg/ml to 3.9 ± 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V₁ receptors. However, the YM087-induced antagonism of V₁ receptors was less pronounced than V₂ receptor blockade. Conclusion: These data show that YM087 is an effective dual V₁/V₂ receptor antagonist in man. Received: 17 February 1999 / Accepted in revised form: 18 August 1999     

Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery

Objective: A new formulation of propofol 6% in Lipofundin MCT/LCT 10% (propofol 6% SAZN) has been developed in order to reduce the fat, emulsifier and volume load that is given during prolonged infusions of propofol. The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). Methods: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery. Results: The average pharmacokinetic parameter estimates of clearance (Cl), volume of distribution at steady state (V_d,ss), elimination half-life (t _1/2,β) and distribution half-life (t _1/2,α) observed in the three groups were 28 ± 1.1 ml/kg/min, 1.8 ± 0.12 l/kg, 94 ± 4.1 min and 3.1 ± 0.26 min, respectively (mean ± SEM, n=24) and no significant differences were noted between the three formulations (P > 0.05). In one patient receiving propofol 6% SAZN, in two patients receiving propofol 1% SAZN and in three patients receiving Diprivan-10, the level of sedation was inadequate and additional sedative medication had to be given. In all other 18 patients, the level of sedation was adequate. The mean propofol concentration in these six inadequately sedated patients was lower than the adequately sedated patients (P=0.015). The serum triglyceride concentrations were not significantly different between the groups studied. No adverse events occurred in any of the patients. Conclusions: The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN are in good agreement with those of the 1% formulations. Propofol 6% SAZN therefore provides a useful alternative to the commercially available 1% formulation for short-term sedation in the intensive care unit. Expected advantages in long-term sedation of the 6% over 1% formulation are the subject of an ongoing study. Received: 11 June 1999 / Accepted in revised form: 23 December 1999     

High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfotiamine

Objective: The influence of either orally administered S-benzoylthiamine-O-monophosphate (benfotiamine) or thiamine nitrate on the thiamine status was tested in a randomised, two-group comparison study in 20 end-stage renal disease (ESRD) patients. Main outcome measures were the pharmacokinetics of thiamine diphosphate (TDP) in blood, the in vitro erythrocyte transketolase activity, its activation coefficient (α-ETK) and the TDP concentration in erythrocytes. Methods: After ingestion of a single dose of either 100 mg thiamine nitrate (corresponding to 305 μmol thiamine) or 100 mg benfotiamine (corresponding to 214 μmol thiamine), the blood levels of thiamine phosphate esters were analysed by means of high-performance liquid chromatography for a 24-h period. The TDP concentration in erythrocytes was calculated using the haematocrit and TDP concentration in blood. Erythrocyte transketolase activity and α-ETK were measured before and 10 h after administration. The pharmacokinetics of TDP in blood were compared with healthy subjects of other studies retrieved from database query. Results: Regarding the blood concentrations of TDP, the patients with ESRD had a 4.3 times higher area under the concentration–time curve after benfotiamine administration than after thiamine nitrate. After benfotiamine administration, the peak plasma concentration of TDP exceeded that in healthy subjects by 51%. In the ESRD patients, after 24 h, the mean TDP concentration in erythrocytes increased from 158.7 ± 30.9 ng/ml initially to 325.8 ± 50.9 ng/ml after administration of benfotiamine and from 166.2 ± 51.9 ng/ml to 200.5 ± 50.0 ng/ml after thiamine nitrate administration. The ratio between the maximum erythrocyte TDP concentration and basal concentration was 2.66 ± 0.6 in the benfotiamine group and 1.44 ± 0.2 in the group receiving thiamine nitrate (P < 0.001). After 24 h, it was 2.11 ± 0.4 and 1.23 ± 0.2, respectively. The transketolase activity increased from 3.54 ± 0.7 μkat/l initially to 3.84 ± 0.6 μkat/l after benfotiamine intake (P=0.02) and from 3.71 ± 0.8 μkat/l to 4.02 ± 0.7 μkat/l after thiamine nitrate intake (P=0.08). Likewise, α-ETK decreased from initially 1.10 ± 0.07 to 1.04 ± 0.04 (P=0.04) and from 1.12 ± 0.05 to 1.08 ± 0.06 (P=0.09). After 24 h, the phosphorylation ratio in whole blood decreased from 12.9 ± 6.9 initially to 5.6 ± 3.2 after benfotiamine administration (P=0.02) and from 13.5 ± 7.3 to 9.0 ± 4.8 (P=0.03) after administration of thiamine nitrate. No correlation between erythrocyte TDP concentration and transketolase activity and/or α-ETK was observed in ESRD patients, either before or 10 h after administration. Conclusion: Compared with thiamine nitrate, the oral administration of benfotiamine leads to higher TDP concentrations in erythrocytes accompanied with a significant improvement of the erythrocyte transketolase activity in ESRD patients. Received: 4 October 1999 / Accepted: 15 March 2000     

Quinolone-induced arthropathy: exposure of magnesium-deficient aged rats or immature rats, mineral concentrations in target tissues and pharmacokinetics

Quinolone treatment or magnesium deficiency induce identical cartilage lesions in juvenile rats and show additive arthropathogenic effects. It has been shown previously that neither condition is arthropathogenic in 8-week-old rats. Joint cartilage from aged individuals is rather prone to pathological alterations but information on prolonged quinolone treatment and/or dietarily induced magnesium deficiency in aged animals is not available. We treated magnesium-deficient (n = 9) aged Wistar rats (age 15 months) and age-matched controls with daily doses of 600 mg ofloxacin/kg body wt. by gastric intubation for 28 days. Further groups of magnesium-deficient and control rats (n = 9 and n = 10, respectively) received the vehicle only. Peak plasma concentrations of ofloxacin in adult rats were 20.5 ± 5.6 mg/l (mean ± SD) following treatment with a single dose of 600 mg/kg body wt. At the end of the experiment the degree of magnesium deficiency was most pronounced in plasma (Mg²⁺-def., 0.33 ± 0.12 mmol/l; control, 0.97 ± 0.08 mmol/l) and less pronounced in sternal cartilage (Mg²⁺-def., 10.8 ± 3.6 mmol/kg dry wt; control, 13.3 ± 2.8 mmol/kg dry wt), whereas the magnesium concentration in femoral bone remained unchanged (Mg²⁺-def., 201 ± 13 mmol/kg dry wt; control, 204 ± 11 mmol/kg dry wt). Histological investigation of the knee joints revealed no cartilage lesions following ofloxacin treatment, magnesium deficiency or a combination of both conditions. By contrast, cartilage lesions such as scars and erosions of the joint surface, chondrocyte clusters within acellular areas of the cartilage matrix and persisting clefts were detectable in knee joints from 7 of 10 adult rats (age 9 months) which had been treated with 4 × 600 mg fleroxacin/kg body wt. at 5 weeks of age. Mean plasma concentration of fleroxacin in juvenile rats was approx. 50 mg/l between 1.5 and 6 h after dosing and the drug was still detectable in plasma 48 h after dosing (0.4 ± 0.1 mg/l). Our data indicate that joint cartilage in aged rats is not altered by a 4-week quinolone treatment, even during magnesium deficiency. Cartilage lesions in adult rats were only detectable if the animals had been treated during the sensitive phase at 5 weeks postnatally. Received: 3 March 1997 / Accepted: 15 May 1997     

Serum and urinary boron levels in rats after single administration of sodium tetraborate

The pharmacokinetics of boron was studied in rats by administering a 1 ml oral dose of sodium tetraborate solution to several groups of rats (n=20) at eleven different dose levels ranging from 0 to 0.4 mg/100 g body weight as boron. Twenty-four-hour urine samples were collected after boron administration. After 24 h the average urinary recovery rate for this element was 99.6 ± 7.9. The relationship between boron dose and excretion was linear (r=0.999) with a regression coefficient of 0.954. This result suggests that the oral bioavailability (F) of boron was complete. Another group of rats (n=10) was given a single oral injection of 2 ml of sodium tetraborate solution containing 0.4 mg of boron/100 g body wt. The serum decay of boron was followed and found to be monophasic. The data were interpreted according to a one-compartment open model. The appropriate pharmacokinetic parameters were estimated as follows: absorption half-life, t _1/2a=0.608±0.432 h; elimination half-life, t _1/2=4.64±1.19 h; volume of distribution, Vd=142.0±30.2 ml/100 g body wt.; total clearance, C _tot=0.359 ± 0.0285 ml/min per 100 g body wt. The maximum boron concentration in serum after administration (C _max) was 2.13 ± 0.270 mg/l, and the time needed to reach this maximum concentration (T _max) was 1.76 ± 0.887 h. Our results suggest that orally administered boric acid is rapidly and completely absorbed from the gastrointestinal tract into the blood stream. Boric acid in the intravascular space does not have a strong affinity to serum proteins, and rapidly diffuses to the extravascular space in proportion to blood flow without massive accumulation or binding in tissues. The main route of boron excretion from the body is via glomerular filtration. It may be inferred that there is partial tubular resorption at low plasma levels. The animal model is proposed as a useful tool to approach the problem of environmental or industrial exposure to boron or in cases of accidental acute boron intoxication. Received: 1 December 1997 / Accepted: 24 March 1998     

Short- and long-term treatments with iloprost in diabetic patients with peripheral vascular disease: effects on the cardiovascular risk factor plasminogen activator inhibitor type-1

Objectives: Iloprost, an analogue of prostacyclin, is often utilised in subjects with diabetes mellitus complicated by macroangiopathy. Methods: The effects of iloprost infusion on plasminogen activator inhibitor type-1 (PAI-1), glucometabolic control and cardiovascular equilibrium in patients with type-2 diabetes mellitus and peripheral arterial occlusive disease were investigated. Thirteen (7 men/6 women) normal-weight, normotensive and non-smoker type-2 diabetic patients (63.8 ± 3.4 years, mean ± SD) with peripheral arterial occlusive disease, stage-II according to Fontaine classification, were enrolled. Eight (four men/four women) patients underwent three study designs, each separated by a 1-week interval: study I, infusion of iloprost (3 ng kg⁻¹ min⁻¹ for 5 h) for 1 day alone (short-term treatment); study II, infusion of saline (for 5 h) for 1 day (control treatment); study III, infusion of iloprost (3 ng kg⁻¹ min⁻¹ for 5 h) over a period of 28 days (long-term treatment). The remaining five (three men/two women) patients underwent study IV only, infusion of saline over a period of 28 days (placebo treatment). Plasma levels of glucose, plasminogen, PAI-1 activity and fibrinogen, blood pressure and heart rate were determined in all studies, while plasma insulin levels, blood HbA_1c, walking distance and Winsor index only in studies III and IV. Results: Both short- and long-term treatments with iloprost significantly reduced PAI-1 activity (baseline vs end: 17.4 ± 1.9 AU/ml vs 15.0 ± 1.6 AU/ml, P < 0.02; 20.5 ± 7.6 AU/ml vs 7.9 ± 2.1 AU/ml, P < 0.002, respectively). Long-term treatment with iloprost significantly increased walking distance (baseline vs end: 325 ± 41 m vs 496 ± 52 m, P < 0.0001), but not Winsor index. Neither glucometabolic control nor cardiovascular equilibrium were affected by short- and long-term treatments with iloprost. Control and placebo treatments did not cause any significant modifications in the parameters evaluated. Conclusion: If confirmed by further investigations, the results of this pilot study suggest that iloprost, infused for both brief and long periods, is able to reduce the cardiovascular risk factor PAI-1, increases free walking capacity and does not affect glucometabolic control and blood pressure in type-2 diabetic patients complicated by macroangiopathy. Received: 25 August 1998 / Accepted in revised form: 8 June 1999     

Terbinafine increases the plasma concentration of paroxetine after a single oral administration of paroxetine in healthy subjects

Objective Paroxetine is believed to be a substrate of CYP2D6. However, no information was available indicating drug interaction between paroxetine and inhibitors of CYP2D6. The aim of this study was to examine the effects of terbinafine, a potent inhibitor of CYP2D6, on pharmacokinetics of paroxetine. Methods Two 6-day courses of either a daily 150-mg of terbinafine or a placebo, with at least a 4-week washout period, were conducted. Twelve volunteers took a single oral 20-mg dose of paroxetine on day 6 of both courses. Plasma concentrations of paroxetine were monitored up to 48 h after dosing. Results Compared with the placebo, terbinafine treatment significantly increased the peak plasma concentration (C_max) of paroxetine, by 1.9-fold (6.4 ± 2.4 versus 12.1 ± 2.9 ng/ml, p < 0.001), and the area under the plasma concentration-time curve from zero to 48 h [AUC (0–48)] of paroxetine by 2.5-fold (127 ± 67 vs 318 ± 102 ng/ml, p < 0.001). Elimination half-life differed significantly (15.3 ± 2.4 vs 22.7 ± 8.8 h, p < 0.05), although the magnitude of alteration (1.4-fold) was smaller than C_max or AUC. Conclusion The present study demonstrated that the metabolism of paroxetine after a single oral dose was inhibited by terbinafine, suggesting that inhibition of CYP2D6 activity may lead to a change in the pharmacokinetics of paroxetine. However, further study is required to confirm this phenomenon at steady state.     

Vancomycin dosing in morbidly obese patients

Objectives and methods: Vancomycin hydrochloride dosing requirements in morbidly obese patients with normal renal function were computed to determine the dose of vancomycin necessary to achieve target steady-state peak and trough concentrations and compared with a normal weight population. Results: Morbidly obese patients [total body weight (TBW) 165 kg, ideal body weight (IBW) 63 kg] required 31.2 mg · kg⁻¹ · d⁻¹ TBW or 81.9 mg · kg⁻¹ · d⁻¹ IBW to achieve the target concentrations. Normal weight patients (TBW 68.6 kg) required 27.8 mg · kg⁻¹ · d⁻¹ to achieve the same concentrations. Because of altered kinetic parameters in the morbidly obese patients (obese: t1/2=3.3 h, V=52 l, CL =197 ml · min⁻¹; normal: t1/2=7.2 h, V=46 l, CL=77 ml · min⁻¹, 20 of 24 patients required q8h dosing (1938 mg q8h) compared with q12h dosing (954 mg q12h) in all normal weight patients in order to avoid trough concentrations that were too low for prolonged periods. There was a good correlation between TBW and CL, but only fair correlation between TBW and V. Conclusion: Doses required to achieve desired vancomycin concentrations are similar in morbidly obese and normal weight patients when TBW is used as a dosing weight for the obese (approximately 30 mg · kg⁻¹ · d⁻¹). Shorter dosage intervals may be needed when dosing morbidly obese patients so that steady-state trough concentrations remain above 5 μg · ml⁻¹ in this population. Because of the large amount of variation in required doses, vancomycin serum concentrations should be obtained in morbidly obese patients to ensure that adequate doses are being administered. Dosage requirements for morbidly obese patients with renal dysfunction require further study. Received: 9 March 1998 / Accepted in revised form: 30 June 1998     

Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function

Objective: The influence of liver disease on the pharmacokinetics of candesartan, a long-acting selective AT₁ subtype angiotensin II receptor antagonist was studied. Methods: Twelve healthy subjects and 12 patients with mild to moderate liver impairment received a single oral dose of 12 mg of candesartan cilexetil on day 1 and once-daily doses of 12 mg on days 3–7. The drug was taken before breakfast. Serial blood samples were collected for 48 h after the first and last administration on days 1 and 7. Serum was analyzed for unchanged candesartan by HPLC with UV detection. Results: The pharmacokinetic parameters on days 1 and 7 revealed no statistically significant influence of liver impairment on the pharmacokinetics of candesartan. Following single dose administration on day 1, the␣mean␣C_max was 95.2 ng · ml⁻¹ in healthy subjects and 109 ng · ml⁻¹ in the patients. The AUC_0−∞ was␣909 ng.h · ml⁻¹ in healthy volunteers and 1107 ng.h · ml⁻¹ in patients and the elimination half-life was 9.3 h in healthy volunteers and 12 h in the patients. At steady state on day 7, mean C_max values were similar in both groups (112 vs 116 ng · ml⁻¹); the AUC_τ was 880 ng.h · ml⁻¹ in healthy subjects and 1080 ng.h · ml⁻¹ in patients while the elimination half-life was 10 h in healthy subjects and 12 h in the patients with liver impairment. The AUC_0−∞ on day 1 was almost identical to the AUC_τ on day 7. A moderate drug accumulation of 20%, which does not require a dose adjustment, was observed following once-daily dosing in both groups. No serious or severe adverse events were reported. Conclusion: Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients. Received: 24 November 1997 / Accepted in revised form: 18 February 1998     

The effects of acute falciparum malaria on the disposition of caffeine and the comparison of saliva and plasma-derived pharmacokinetic parameters in adult Nigerians

Objectives: The pharmacokinetics of caffeine and its dimethylxanthine metabolites were evaluated in Nigerians, for whom it is normal to consume caffeine-containing beverages during ill health and recuperation in the belief that caffeine aids early recovery from illness; however, there are no data defining the kinetics of caffeine in healthy and ill Nigerians. Materials and methods: A single oral dose of 300 mg caffeine was given to ten healthy adult Nigerians and ten adults suffering from acute uncomplicated Plasmodium falciparum malaria infection. Caffeine and its dimethylxanthine metabolites were measured in plasma and saliva of healthy subjects and in plasma of patients suffering from malaria using high-performance liquid chromatography. Results: The plasma pharmacokinetics of caffeine per se in both groups was similar (P > 0.05). The maximum plasma concentration (C_max) of paraxanthine was significantly lower (P < 0.05) in malaria (0.9 ± 0.4 μg/ml) than in healthy controls (1.4 ± 0.5 μg/m1), and the paraxanthine:caffeine area under the plasma concentration–time curve ratio, an index of cytochrome P₄₅₀ (CYP)IA2 activity was significantly lower (P < 0.05) in malaria patients (0.5 ± 0.1) than in healthy controls (0.3 ± 0.2). The elimination half-life of theophylline was longer in malaria, while the area under the plasma concentration–time curve of theobromine was significantly higher (P < 0.05) in malaria (7.1 ± 3.4 μg ml⁻¹ h) than in healthy adults (4.1 ± 2.2 μg ml⁻¹ h). Excellent correlations were found between saliva and plasma concentrations of caffeine (r ²=0.98) with a mean saliva:plasma concentrations ratio of 0.7 ± 0.1. The plasma concentrations (C_max and AUC) were therefore higher than the corresponding salivary levels, so that the apparent oral clearance calculated for saliva exceeded the true oral clearance based on plasma data. Conclusions: Acute Plasmodium falciparum malaria produced significant changes in the disposition of caffeine metabolites. Analysis of concentrations in saliva is a useful non-invasive method for monitoring the kinetics of caffeine and paraxanthine in Nigerians. Received: 14 April 1999 / Accepted in revised form: 30 November 1999     

The pharmacokinetics of caffeine in Nigerian children suffering from malaria and kwashiorkor

Objectives: Caffeine-containing beverages are generally consumed by Nigerians suffering from malaria and kwashiorkor in the belief that caffeine aids early recovery from these illnesses, which are common in the tropics. However, there are no studies on the influence of these diseases on the absorption and pharmacokinetics of caffeine in Africans. Materials and methods: A single oral dose of caffeine was given to five healthy children and to five and seven children suffering from malaria and kwashiorkor, respectively. Caffeine and its dimethylxanthine metabolites were measured in plasma using high-performance liquid chromatography. Results: The maximum plasma concentration (C_max) of caffeine and the time of C_max were similar (P > 0.05) in the three groups. However, the elimination half-life of caffeine was significantly longer in children with malaria (9.2 ± 3.5 h) (P < 0.01) and kwashiorkor (13.1 ± 7.9 h) (P < 0.05) than in the healthy controls (3.7 ± 1.8 h). The total plasma oral clearance of caffeine of 4.4 ± 1.9 ml/min/kg in healthy children was significantly higher (P < 0.01) than in those with kwashiorkor (2.0 ± 0.9 ml/min/kg) and malaria (1.6 ± 1.0 ml/min/kg) (P < 0.05). Paraxanthine was the principal metabolite in all the three groups with C_max significantly higher in healthy children (1.3 ± 0.3 μg/ml) than in children with malaria (0.8 ± 0.4 μg/ml) (P < 0.05) and kwashiorkor (0.3 ± 0.1 μg/ml) (P < 0.0001). CYP1A2 activity, measured by the plasma ratios of paraxanthine: caffeine, was significantly lower in kwashiorkor and malaria. Conclusions: This study showed that the plasma kinetics of caffeine are significantly altered in malaria and kwashiorkor, and CYP1A2 activity was lower in these two disease groups. Received: 12 April 1999 / Accepted in revised form: 30 November 1999     

ANP is cleared much faster than BNP in patients with congestive heart failure

Objective To obtain a better understanding of the pharmacokinetics of atrial and brain natriuretic peptides (ANP and BNP, respectively), two peptide mediators used in the treatment of congestive heart failure (CHF). Although both peptides exert their effects by binding to a common receptor (natriuretic peptide receptor A) with about the same affinity, their respective loading and maintenance doses differ. Methods Sixteen CHF patients were randomized to be infused for 2 h with α-human ANP (0.05 μg/kg per minute) or BNP (0.01 μg/kg per minute). Plasma concentrations of both peptides were measured 0, 2, 5, 15, 30, 60 and 120 min post-infusion. The pharmacokinetic parameters were then calculated using a 1-compartment model. Results The plasma BNP concentrations in the ANP and BNP groups before infusion were 464.7 ± 339.8 and 506.8 ± 332.5 pg/ml, respectively. Following infusion, ANP disappeared from the circulation more rapidly than BNP: their plasma half-lives were 2.4 ± 0.7 and 12.1 ± 3.0 min, and their total body clearance volumes were 48.2 ± 24.1 and 10.1 ± 2.7 ml/min per kilogram, respectively. Conclusion ANP has a shorter half-life in the plasma of CHF patients than BNP, which suggests that it controls hemodynamics more readily than BNP.     

Pharmacokinetics of oxypolygelatine in healthy volunteers

Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg⁻¹ body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml⁻¹, the area under the plasma concentration/time curve (AUC_0∞) was calculated to 70.135 (15.861) μg · h · ml⁻¹. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cl_tot) of 24.6 (6.8) ml · min⁻¹. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites. Received: 9 June 1998 / Accepted in revised form: 23 November 1998     

Pharmacokinetics of intravenous ATP in cancer patients

Objective: To characterise the pharmacokinetics of adenosine 5′-triphosphate (ATP) in patients with lung cancer after i.v. administration of different ATP dosages. Methods: Twenty-eight patients received a total of 176 i.v. ATP courses of 30 h. Fifty-two infusions were given as low-dose infusions of 25–40 μg kg⁻¹ min⁻¹, 47 as middle-dose infusions of 45–60 μg kg⁻¹ min⁻¹ and 77 as high-dose infusions of 65–75 μg kg⁻¹ min⁻¹ ATP. Kinetic data of ATP concentrations in erythrocytes were available from 124 ATP courses. Results are expressed as mean ± SEM. Results: Most ATP courses in cancer patients were without side effects (64%), and side effects occurring in the remaining courses were mild and transient, resolving within minutes after decreasing the infusion rate. Baseline ATP concentration in erythrocytes was 1554 ± 51 μmol l⁻¹. ATP plateau levels at 24 h were significantly increased by 53 ± 3, 56 ± 3 and 69 ± 2% after low-dose, middle-dose and high-dose ATP infusions, respectively. At the same time, significant increases in plasma uric acid concentrations were observed: 0.06 ± 0.01, 0.11 ± 0.01 and 0.16 ± 0.01 mmol l⁻¹, respectively. The mean half-time for disappearance of ATP from erythrocytes, measured in five patients, was 5.9 ± 0.5 h. Conclusions: During constant i.v. infusion of ATP in lung cancer patients, ATP is taken up by erythrocytes and reaches dose-dependent plateau levels 50–70% above basal concentrations at approximately 24 h. Received: 7 July 1999 / Accepted in revised form: 30 December 1999     

Measurement of furancarboxylic acid, a candidate for uremic toxin, in human serum, hair, and sweat, and analysis of pharmacological actions in vitro

3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), a candidate for uremic toxin, was measured in human hair for examining a possible utility as indicator of renal dysfunction. The serum concentration of CMPF was much higher (32.3 ± 2.7 μg/ml, n=17; mean ± SEM) in uremic patients aged 40–55 years receiving hemodialysis treatment than in healthy younger subjects (3.61 ± 0.19 μg/ml, n=22), aged 18–23 years. However, the hair concentration of CMPF tended to be lower in the patients (6.8 ± 1.7 ng/10 mg hair) than in the healthy younger subjects (15.8 ± 4.5 ng/10 mg) and was significantly lower than that in the healthy age-matched subjects (22.4 ± 5.3 ng/10 mg, n=12), aged 40–47 years. Since CMPF was measurable in the sweat (4.4 ± 3.7 ng/mg) collected from six out of seven healthy subjects examined, it was suggested that the contribution of sweat to the measurement of CMPF in hair was considerable. The fact that the uremic patients undergoing hemodialysis therapy had less sweat than healthy subjects may explain the lower concentration of CMPF in the patients' hair. The pathophysiological roles of CMPF in the body were attempted to be explored by using excised guinea pig organs, and human platelets and neutrophils. CMPF showed no remarkable effects in the concentration range of ≤10⁻⁴ M except for only slight suppression of spontaneous contracture of guinea pig tenia coli at 10⁻⁴ M. As far as the organs and tissues examined in the present study are concerned, the biological activity of CMPF itself, if any, may be very weak. Precaution should be taken against the delivery of a substance through sweat to hair when a small amount of substance is attempted to be measured in hair by employing a sensitive analytical method. Received: 14 September 1999 / Accepted: 3 November 1999     

Biological monitoring of standardized exposure to ethylbenzene: evaluation of a biological tolerance (BAT) value

The results of standardized 8 h lasting exposures of n=18 volunteers to ethylbenzene (EthBz) at levels of 25 and 100% of the maximum allowable concentrations at the workplace (MAK) value of 100 ppm as well as the results of field studies are considered to evaluate a biological tolerance (BAT) value for EthBz. On the basis of the relationship between the external and internal exposure a BAT value of 1.5 mg/l has been set for the EthBz concentration in blood as the most sensitive and specific parameter of exposure to this aromatic hydrocarbon. The interpretation of EthBz blood values has to take into account the short half-life of t _1/2=0.5 ± 0.08 h in the first hour after the end of exposure in which this aromatic hydrocarbon is eliminated from the blood. The additional determination of the EthBz metabolites mandelic acid (MA) and phenylglyoxylic acid (PGA), respectively, excreted in post shift urine as well as in urine samples at the beginning of the next shift shows good correlations with the external exposure. The biological half-life of MA was calculated to t _1/2=5.3 ± 1.1 h. Because the time of sampling can vary the relationship between the levels of MA to PGA the total concentration of the excreted metabolites depends less on this influence and is therefore better suited for monitoring exposed persons. On the basis of the standardized experiments a BAT value has been proposed of 2 g MA plus PGA corrected per gram creatinine. Both BAT values are adjusted to data which result from earlier standardized exposures during 30 min to EthBz under physical activity of 50 watt on a bicycle ergometer. Received: 10 August 1999 / Accepted: 2 November 1999