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     

Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

   Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg⁻¹ sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg⁻¹ · min⁻¹, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min⁻¹ · kg⁻¹), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg⁻¹) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean C_max values of 421 (group I), 125 (group II), and 53 (group III) ng · ml⁻¹ and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg⁻¹ tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate. Received: 23 August 1995 / Accepted in revised form: 19 August 1996     

Pharmacokinetics and tolerability of oral iloprost in thromboangiitis obliterans patients

Objective: Iloprost is a potent PGI₂ mimetic, which has been shown to be therapeutically effective in several vascular disorders. Due to its rapid clearance from the central compartment, iloprost is administered mainly by i.v. infusion, which limits its use to hospitalized patients. In order to improve pharmacotherapeutic use of this PGI₂ mimetic, an oral extended-release (ER) dosage form has been developed, which should mimic plasma level profiles as observed after i.v. infusion and serve as a therapeutic equivalent. Methods: This trial was performed to investigate the tolerability and pharmacokinetics of iloprost administered perorally, compared with i.v. infusion, in 12 patients suffering from thromboangiitis obliterans (TAO). A dose titration was carried out for 1 week with i.v. iloprost, followed by a p.o. titration and treatment phase of 3 weeks' duration. Pharmacokinetics was investigated at the individually tolerated dose levels; i.e., on days 5–7 (i.v. infusion at 2, 2.5 and 3 ng · kg⁻¹ · min⁻¹), and twice during p.o. treatment after b.i.d. administration of 50, 100, 150, 200 or 300 μg. Results: Individual tolerability of iloprost varied: 7 patients out of 12 tolerated the maximum i.v. dose of 3 ng · kg⁻¹ · min⁻¹; six tolerated the maximum oral dose of 600 μg. No patients withdrew from the study due to adverse events. Flush and headache were the most common adverse events and seemed to be related to the study drug. After i.v. infusion of iloprost, dose-normalized (3 ng · kg⁻¹ · min⁻¹), steady-state plasma levels were 260 pg · ml⁻¹. Terminal half-life was 0.57 h. Total clearance ranged from 8 to 17 ml · min⁻¹ · kg⁻¹. Peroral administration of the ER formulation resulted in dose-dependent C_max and AUC values. AUC values of the first and second daily dose interval, i.e., 0–5 h and 5–11 h after first dosing, were almost identical. Absolute bioavailability was 24%, with the exception of two patients who tolerated only 50 μg b.i.d. and exhibited a bioavailability of approx. 60%. The AUC values observed in weeks 2 and 4 were identical, demonstrating low day-to-day variability of iloprost plasma level profiles in TAO patients. Conclusion: Based upon pharmacokinetic data, the ER formulation provides an equivalent to the i.v. infusion of iloprost and broadens the range of therapy to non-hospitalized patients. The availability of capsules with 50 and 100 μg iloprost enables individual dose titration and pharmacotherapy. Beneficial effects, as observed with i.v. iloprost in TAO patients, should therefore be achievable by peroral pharmacotherapy using the new ER formulation. Received: 18 July 1996 / Accepted in revised form: 2 April 1997     

Pharmacokinetics of cloxacillin in patients undergoing hip or knee replacement

Objective: The pharmacokinetics of cloxacillin was investigated in 14 men and 24 women undergoing cemented hip (n = 19; age range 56–90) or knee replacement surgery (n = 19; age range 51–84) for osteoarthritis. Cloxacillin 1 g was given intravenously as a bolus dose at the induction of anesthesia, and plasma samples and urine were collected for 6 h. Drug levels were determined using HPLC. Results: Preoperative serum creatinine levels were 84 μmol · l⁻¹ in hip patients and 72 μmol · l⁻¹ in knee patients. The calculated values for creatinine clearance were 63 and 85 ml · min⁻¹ · 1.73 m⁻², respectively. Total clearance of cloxacillin was 134 ml · min⁻¹ · 1.73 m⁻² in eighteen evaluated patients undergoing hip replacement, and 162 ml · min⁻¹ · 1.73 m⁻² in eighteen patients undergoing knee surgery. Renal clearance was 72 and 79 ml · min⁻¹ · 1.73 m⁻², respectively. Non-renal clearance was 57 ml · min⁻¹ · 1.73 m⁻² in hip patients and 77 ml · min⁻¹ · 1.73 m⁻² in knee patients. Renal clearance of cloxacillin correlated with the estimated creatinine clearance (r = 0.652). Although women received higher doses than men (median 2.02 vs 2.32 mmol · 1.73 m⁻²), there were no sex differences in clearance corrected for body surface area. Conclusion: Total clearance of cloxacillin was lower in patients undergoing hip replacement than in patients undergoing replacement of the knee, but there was no difference between men and women. Received: 7 May 1996 / Accepted in revised form: 15 October 1996     

Pharmacokinetics of imidapril and its active metabolite imidaprilat following single dose and during steady state in patients with chronic renal failure

Objective: An open study on the single dose and steady-state pharmacokinetics of imidapril, a novel prodrug-type angiotensin-converting enzyme (ACE) inhibitor, and its active metabolite imidaprilat was conducted in eight patients with moderate chronic renal failure [mean creatinine clearance (CL_CR) 64 ml · min⁻¹; range 42–77 ml · min⁻¹], eight patients with severe chronic renal failure (mean CL_CR, 18 ml · min⁻¹; range 11–29 ml · min⁻¹) and eight healthy volunteers with normal renal function. Subjects received an oral dose of 10 mg imidapril once per day for 7 days. Results: No statistical differences of either maximum concentration (C_max) or the area under the curve (AUC) were found between patients with moderate renal failure and healthy subjects. However, C_max and AUC for both imidapril and imidaprilat were significantly higher in patients with severe renal impairment than in healthy volunteers. There were no clinically relevant differences among the three subject groups with regard to total urinary excretion of both imidapril and imidaprilat. Conclusion: The smallest imidapril dose which is clinically effective should be used in patients with severe renal insufficiency. Received : 11 July 1997 / Accepted in revised form : 6 October 1997     

Pharmacokinetics and distribution of 6-mercaptopurine administered intravenously in children with lymphoblastic leukaemia

Objective: The pharmacokinetics of 6-mercaptopurine, including cerebrospinal-fluid (CSF) distribution, and the erythrocyte 6-thioguanine nucleotide concentrations were determined in children randomised to receive intravenous mercaptopurine for acute lymphoblastic leukaemia (ALL), according to the EORTC protocol ALL n°58881. Results: After 1 month of oral treatment at a dose of 50 mg · m⁻² · day⁻¹, the pharmacokinetic parameters were determined after the first i.v. administration of 1 g · m⁻² (bolus dose of 0.2 g · m⁻² followed by an 8-h infusion of 0.8 g · m⁻²) in 11 patients: systemic clearance was 23.02 l · h⁻¹, volume of distribution was 0.75 l · kg⁻¹, and elimination half-life was 1.64 h. The erythrocyte thioguanine concentrations were measured in the same 11 patients and increased significantly between the beginning and the end of infusion (10 pmol × 10⁸ packed RBC) or within 24 h of infusion (223 pmol × 10⁸ packed RBC). The CSF concentration was 3.78 μmol · l⁻¹, 1–6 h after the beginning of infusion (n=28) and the CSF to plasma ratio was 0.15 (n=16). In patients receiving the oral dose of 50–165 mg · m⁻² · day⁻¹ of 6-mercaptopurine, CSF concentrations were below 0.18 μmol · l⁻¹, 1–24 h after drug intake (n=67), and the CSF to plasma ratio was not calculated. Conclusion: Following the i.v. administration of 6-mercaptopurine, we observed high CSF concentrations of 6-mercaptopurine and an acute increase of erythrocyte thioguanine nucleotide concentrations. The clinical trial (EORTC protocol ALL n°5881), comparing the oral and i.v. administrations of mercaptopurine, will demonstrate if the i.v. administration reduces the incidence of CNS relapses. Received: 15 August 1996 / Accepted in revised form: 8 April 1997     

Acute effects of celiprolol on muscle blood flow and insulin sensitivity: studies using [15O]-water, [18F]-fluorodeoxyglucose and positron emission tomography

Objective: Recently the role of peripheral vasoconstriction in the aetiology of insulin resistance has been proposed. Celiprolol is a β₁-selective adrenoceptor antagonist with partial agonist activity at the β₂-receptor as well as vasodilator properties. The acute effects of celiprolol on skeletal muscle blood flow and insulin sensitivity were measured in this study. Methods: Celiprolol (2 times 0.5 mg · kg⁻¹) or saline was given intravenously to five healthy males in random order. Muscle blood flow was measured in femoral regions using [¹⁵O]-labelled water and positron emission tomography (PET) during euglycaemic hyperinsulinaemia (serum insulin ˜65 mU · l⁻¹) after an overnight fast. Thereafter, skeletal and heart muscle glucose uptake were determined using [¹⁸F]-2-deoxy-d-glucose. Results: Celiprolol increased muscle blood flow by 74%, from 3.4 to 5.9 ml · min⁻¹ · 100 g⁻¹ muscle in the basal state. It decreased peripheral resistance by 40%, from␣32.0 to 19.2 mmHg · ml⁻¹ · min⁻¹ · 100 g⁻¹. Celiprolol significantly decreased diastolic blood pressure from 82 to 73 mmHg and increased heart rate from 61 to 68 beats · min⁻¹, which suggests sympathetic activation. Insulin-stimulated glucose uptake was reduced by 46% in the whole body, from 39 to 21 μmol · kg⁻¹ · min⁻¹ and by 59% in the femoral muscles, from 99 to 41 μmol · kg⁻¹ · min⁻¹, with celiprolol as compared to saline. The effect on heart glucose uptake did not statistically differ between the treatments. Conclusion: Celiprolol given intravenously increased muscle blood flow and decreased peripheral resistance at rest. It also acutely increased heart rate probably via sympathetic activation, and decreased insulin sensitivity in the muscles of healthy male volunteers. The enhanced muscle perfusion when celiprolol is given intravenously does not explain the improved insulin sensitivity seen in the long-term oral use in dyslipidaemic hypertensive patients. Received: 19 September 1996 / Accepted in revised form: 13 November 1996     

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     

Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and polysulfone dialysers

Objective: The purpose of the present study was to investigate whether the clearance of ceftriaxone during haemodialysis is influenced by the type of membrane used (cuprophane, haemophane or polysulphone). Methods: After administration of a single 2-g dose of ceftriaxone, the half-life of the drug during haemodialysis and the clearance of the dialyser were measured. Results: The mean dialysis clearance normalised for square metre of membrane surface was significantly different for the three dialysers (haemophane 24  ml · min⁻¹ · m⁻²; cuprophane 32 ml · min⁻¹ · m⁻²; polysul phone 42 ml · min⁻¹· m⁻²). Conclusions: Polysulphone membranes are more permeable and increase the extraction of ceftriaxone more than the other dialysers studied (haemophane and cuprophane membranes). These results, taken together with previous data, show that an increase of the dose in dialysis patients treated with large surface (>0.8 m²) and high permeability membranes might be necessary. Received: 18 November 1996 / Accepted in revised form: 12 May 1997     

Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion

Objective: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion. Methods: Eight healthy male volunteers received 1030 nmol · min⁻¹ of clevidipine together with a tracer dose of ³[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days. Results: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l · min⁻¹ · kg⁻¹ and a mean volume of distribution at steady state of 0.6 (0.1) l · kg⁻¹. The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. Conclusion: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The t_max value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short. Received: 23 September 1998 / Accepted in revised form: 20 November 1998     

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery

Objective: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. Methods: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. Results: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 μg · kg⁻¹ · day⁻¹). The total plasma concentration (2.19 vs. 2.43 μg · ml⁻¹), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng · ml⁻¹) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/C_uss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml · kg⁻¹ · h⁻¹). Conclusions: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160␣years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery. Received: 23 August 1996 / Accepted November 11 1996     

Comparison of pharmacokinetics and dynamics of two dosage regimens of foscarnet in AIDS patients with Cytomegalovirus retinitis

Objective: To compare the pharmacokinetics of foscarnet administered as an infusion twice daily (BID) or thrice daily (TID), and to compare the effects on the electrolyte balance, cardiac and renal functions over a 3-week induction treatment of Cytomegalovirus (CMV) retinitis. Methods: Pharmacokinetics/dynamics of foscarnet were investigated on treatment days 1, 14 and 21. Twelve AIDS patients with CMV retinitis completed the investigation period. Concentrations of foscarnet and electrolytes were assayed by high-performance liquid chromatography (HPLC) and by an ion-selective analyser, respectively. Results: The pharmacokinetics of the two regimens were essentially similar. Foscarnet plasma and creatinine clearances were 2.0 and 1.6 ml · min⁻¹ · kg⁻¹, respectively, in the BID group at steady state (day 21). In the TID group the corresponding values were 1.8 and 1.7 ml · min⁻¹ · kg⁻¹, respectively. In both regimens the elimination half-life of foscarnet was 2–3 h. Ionized calcium concentrations were transiently decreased and strongly inversely correlated to foscarnet plasma concentrations in both regimens with no significant differences between groups. A trend towards prolongation of the QTc interval was seen when data from both treatments were analysed together. Conclusion: Our data suggest comparable pharmacokinetics of foscarnet after intermittent administration BID or TID during a 3-week induction period. Received: 22 January 1996 / Accepted in revised form: 6 November 1996     

Chloroquine blood concentrations and malaria prophylaxis in Tanzanian women during the second and third trimesters of pregnancy

Objective: Routine malaria prophylaxis with chloroquine (CQ) is recommended to pregnant semi-immune women in several countries in Africa. The dosage is empirically based. We investigated whether blood CQ concentrations and apparent oral blood clearance (CL/F) change during the course of pregnancy. We also studied whether malaria parasites could be detected together with low CQ blood levels. Methods: Forty nine semi-immune Tanzanian women were recruited in the 16th week of pregnancy. They were given 310 mg oral CQ base once per week as prophylaxis during the whole pregnancy. Capillary blood samples were taken for analysis of CQ before treatment and at weeks 26 and 36. Blood samples were dried on filter paper and analysed by HPLC. Blood was also drawn to detect occurrence of malaria parasites. Results: A total of 25 women fulfilled the sampling schedule. CL/F increased significantly from 160 ml ·  min⁻¹ at week 26 to 180 ml · min⁻¹ at week 36. In 7 of 25 women, CL/F increased >20%. Trough blood CQ concentrations, determined on four occasions at week 26 and at week 36 varied between 200 and 900 nmol · l⁻¹. No statistically significant differences between occasions were seen. Malaria parasites were seen in two individuals early in pregnancy. Conclusion: Blood CQ CL/F showed a small increase during the course of pregnancy. The estimated mean blood CL/F values of 160 and 180 ml · min⁻¹ (week 26 and 36, respectively) were higher than the mean CL/F of 125 ml · min⁻¹ in non-pregnant individuals, published previously. Efficacy of higher dosages of CQ in malaria prophylaxis in pregnant women could, therefore, be evaluated in controlled trials in high-risk malaria areas. Received: 3 July 1996 / Accepted in revised form: 5 November 1996     

Dilatory effects of phosphodiesterase inhibitors on human hand veins in vivo

Objective: To compare the venodilator potencies of the phosphodiesterase (PDE) III inhibitors amrinone and enoximone with the unspecific PDE inhibitors theophylline and pentoxifylline in human hand veins in vivo. Methods: Eighteen healthy nonsmokers (16 men and two women) were studied using the dorsal hand vein technique. After preconstriction with the selective α₁-adrenergic-receptor agonist phenylephrine dose–response curves were constructed for amrinone (1–270 μg · min⁻¹), enoximone (1–270 μg · min⁻¹), theophylline (5–1500 μg · min⁻¹) and pentoxifylline (2–877 μg · min⁻¹) in a random order on separate occasions. Due to limitation in the maximum dose infused in order to avoid systemic effects, full dose–response curves could not be constructed for pentoxifylline. In this case, the individual dose of pentoxifylline and theophylline producing 50% venodilation were compared. Results: All PDE inhibitors induced dose-dependent venodilation. The value of maximum venodilation was the same for amrinone, enoximone and theophylline. The infusion rate needed to induce 50% of maximum venodilation (ED₅₀) was not significantly different for amrinone (geometric mean, 8.8 μg · min⁻¹) and enoximone (14.2 μg · min⁻¹), whereas the ED₅₀ of theophylline (84.0 μg · min⁻¹) was significantly higher than either amrinone or enoximone. The dose necessary to dilate the vein to 50% the maximum dilation (as determined during sodium chloride infusion) was significantly higher for pentoxifylline than for theophylline (409 vs 71 μg · min⁻¹). Conclusions: These findings demonstrate that enoximone and amrinone have similar venodilatory potency which is six times higher than that of theophylline. The least potent vasodilator in this study was pentoxifylline. Received: 16 September 1997 / Accepted in revised form: 4 December 1997     

Renal handling of drugs in the healthy elderly Creatinine clearance underestimates renal function and pharmacokinetics remain virtually unchanged

Objective: It is commonly assumed that renal function, and in parallel the excretion of drugs, is considerably reduced in the elderly. Endogenous creatinine clearance or indirect estimates of this parameter are generally recommended for adapting drug dosage. The present study evaluates the validity of both assumptions. Methods: We compared pharmacokinetics (and pharmacodynamics) of 50 mg atenolol, 800 mg piracetam and 25 mg hydrochlorothiazide plus 50 mg triamterene in ten healthy young [25 (2) years] and 11 healthy elderly subjects [68 (5) years]. Inulin (C_in) and para-aminohippurate [PAH (C_PAH)] clearance (infusion clearance technique), endogenous (C_Cr) and calculated (Cockroft-Gault) creatinine clearance, analysis of drugs and their metabolites (HPLC), were performed. Renal haemodynamics and the pharmacokinetics of β-adrenergic blocking agent, diuretics and the nootropic agent piracetam, respectively, were measured on separate days. Results: C_in was significantly (P < 0.01) lower in the healthy elderly subjects [104 (12) vs 120 (14) ml · min⁻² · 1.73 m⁻² in the young], but remained within the normal range (>90 ml · min⁻² · 1.73 m⁻²). In contrast, C_Cr was even lower in healthy elderly subjects [95 (24) vs 121 (20) ml · min⁻¹ in the young], and the Cockroft-Gault clearance underestimated true glomerular filtration rate (GFR) even more seriously [74 (17) vs 122 (16) ml · min⁻¹]. For atenolol the mean area under the curve (AUC) was similar in both groups [3.16 (0.48) μg · h⁻¹ · ml⁻¹ in the elderly vs 3.01 (0.30) in the young], as was the mean maximal plasma concentration [0.42 (0.07) vs 0.44 (0.06) μg · ml⁻¹], but the proportion of the drug excreted in urine was marginally (P < 0.025) lower in the elderly. Similar results were obtained for hydrochlorothiazide, whereas no marked differences between the groups were found for triamterene and its metabolite. Furthermore, the pharmacodynamic action of diuretics was not significantly altered in the elderly. Conclusions: The true GFR of the healthy elderly remains within the normal range and is underestimated by creatinine clearance and more so by its surrogate (Cockroft-Gault clearance). In parallel, pharmacokinetics of renally excreted drugs are not affected in the healthy elderly to a clinically significant extent. For drugs with a narrow therapeutic window, indirect estimates of GFR appear to be an unreliable means for calculating correct dosage in the elderly. Received: 2 April 1998 / Accepted in revised form: 19 October 1998     

Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults

Objective: The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate (FP) and budesonide (BUD) on adrenocortical activity in asthmatic patients. Methods: Ten asthmatic patients with a mean age of 31.2 years, a mean forced expiratory volume in 1 s (FEV₁) of 91% predicted and a forced mid-expiratory flow (FEF_25–75) of 62.3% predicted were studied in a single-blind randomised crossover design comparing placebo (PL), FP (375 μg per day and 750 μg per day) and BUD (400 μg per day and 800 μg per day) all given once daily for 4 days at each dose via a pressurised metered dose inhaler (pMDI) at 0800 hours. After 4 days of treatment, plasma cortisol was measured at 0800 hours (24 h after the last dose) and a 10-h overnight urine collection was taken, 14 h after the last dose (2200–0800 hours) for analysis of cortisol and creatinine excretion. Results: Plasma cortisol levels (nmol · l⁻¹, as geometric mean) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD (424.1 vs 510.3 nmol · l⁻¹, respectively) but not between the low doses (506.8 vs 514.9 nmol · l⁻¹; PL 532.2 nmol · l⁻¹). For the highest dose FP (750 μg) this equated to 20% suppression of 0800 hours plasma cortisol. Likewise, for overnight urinary cortisol output (nmol · 10 h⁻¹, as geometric mean), there was a significant difference at the high doses of FP and BUD (25.5 vs 38.2 nmol · 10 h⁻¹), but not at the low doses 31.3 vs 34.8 nmol · 10 h⁻¹; PL 32.0 nmol · 10 h⁻¹. For the overnight urinary cortisol/creatinine ratio (nmol · mmol⁻¹, as geometric mean) there was a similar trend; 4.5 vs 6.1 nmol · mmol⁻¹ for high dose and 5.6 vs 6.3 nmol · mmol⁻¹ for low dose; PL 5.9 nmol · mmol⁻¹. Conclusion: Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily, when comparing effects on plasma cortisol levels at 0800 hours, 24 h after the last dose, as well as effects on overnight urinary cortisol output. Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression. Received: 29 April 1997 / Accepted in revised form: 5 July 1997     

Multidrug resistance modulation in vivo: The effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia

Objective: To determine the effect of the coadministration of the multidrug resistance (MDR) modulators cyclosporin A (CyA) alone or plus dexverapamil (D-Ver) on idarubicin (IDA) pharmacokinetics in patients with acute leukemia. Methods: Pharmacokinetic studies were performed in 27 patients with a diagnosis of acute myelogenous leukemia (AML), who were being treated with a combination chemotherapy regimen including idarubicin and cytarabine for the induction of a first remission (n = 14), or of a second remission (n = 7), or for remission consolidation (n = 6). Of these 27 patients, nine were coadministered CyA and seven were coadministered CyA plus D-Ver as MDR modulators. Blood was sampled at appropriate intervals after each of the three IDA daily administrations. IDA and idarubicinol (IDAOL) were assayed by HPLC. Pharmacokinetic evaluations were performed by means of a two-compartment open model with zero-order absorption and first-order elimination using the WinNonlin pharmacokinetic software package. Results: CyA markedly increased the area under the concentration time-curve (AUC) of both IDA [558.26 (197.25) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; P < 0.01] and IDAOL [2896.60 (736.38) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.001] when coadministered as a single modulator, due to a lower total body clearance (CL) [83.51 (52.44) l · h⁻¹ · m⁻² vs 139.65 (69.45) l · h⁻¹ · m⁻²; NS]. When patients received two MDR modulators simultaneously (D-Ver plus CyA), IDA exposure was essentially the same as in those of the no inhibitor group [331.29 (95.49) μg · h · l⁻¹ vs 315.44 (158.28) μg · h · l⁻¹; NS], whereas the IDAOL total body exposure was greater than in the no inhibitor group [2030.32 (401.11) μg · h · l⁻¹ vs 1028.49 (603.95) μg · h · l⁻¹; P < 0.01], even if less than in patients receiving CyA as a single MDR modulator (IDA + CyA group) [AUC 2030.32 (401.11) μg · h · l⁻¹ vs 2896.60 (736.38) μg · h · l⁻¹; P < 0.05], suggesting an antagonistic effect against those of CyA on IDA and IDAOL elimination and/or an unpredictable redistribution. The main pharmacokinetic parameters of IDA, such as CL and volume of distribution at steady state (Vd_ss), were remarkably affected by the coadministration of CyA or CyA plus D-Ver, but no statistically significant difference was noted because of IDA pharmacokinetic interpatient variation. Conclusion: The results show that CyA alone at a dose of 10 mg · kg⁻¹ daily significantly increased systemic body exposure to both IDA and IDAOL in acute leukemia, and suggest that these pharmacokinetic effects were at least partially decreased when D-Ver was coadministered with CyA. Our findings raise important questions concerning the need for a dosage adjustment of IDA when MDR modulators are coadministered. Received: 2 June 1998 / Accepted in revised form: 3 December 1998     

Distribution and metabolism of N G-nitro-l-arginine methyl ester in patients with septic shock

Objective: The pharmacokinetics of N ^G-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. Methods: Blood was sampled at intervals before, during and after 12-h infusion of l-NAME 1 mg · kg⁻¹ · h⁻¹ in nine septic shock patients for determination of plasma concentrations by high-performance liquid chromatography (HPLC). In three patients the renal clearance of the drug was determined. Results: Incubation of l-NAME with plasma and blood in vitro revealed hydrolysis to N ^G-nitro-l-arginine (l-NOARG), the active inhibitor of NO synthesis. l-NOARG did not undergo further degradation. Continuous intravenous infusion of 1 mg · kg⁻¹ · h⁻¹ of l-NAME for 12 h in patients with septic shock increased blood pressure and resulted in increasing plasma concentrations of l-NOARG (C_max 6.2 μg · ml⁻¹ at 12 h) whereas l-NAME concentrations reached a plateau within 1.5 h (C_max 1.0 μg · ml⁻¹). After the infusion was stopped l-NAME disappeared from the plasma rapidly (half-life 19.2 min) whereas l-NOARG concentration declined slowly (half-life 22.9 h). The calculated volume of distribution for l-NAME was 0.45 l · kg⁻¹ body weight and 1.96 l · kg⁻¹ for l-NOARG. The renal clearance for l-NOARG was 3.5% of total body clearance for l-NOARG, whereas l-NAME could not be detected in urine. Conclusion: We conclude that vasoconstriction with l-NAME in septic patients may result from hydrolysis to l-NOARG, the active inhibitor of NO synthesis. The long plasma half-life and large volume of distribution for l-NOARG suggests extensive distribution to extravascular tissues. Since renal excretion is minimal, elimination of the metabolite l-NOARG follows other pathways. Received: 13 March 1998 / Accepted in revised form: 30 June 1998     

Lack of influence of menstrual cycle and premenstrual syndrome diagnosis on pregnanolone pharmacokinetics

Objective: Pregnanolone is a 3α-hydroxylated-5β-reduced metabolite of the female sex steroid hormone progesterone. The compound is currently being evaluated for anaesthetic purposes. Previous studies have indicated a differential physiological response across the menstrual cycle and a different response in patients with premenstrual syndrome (PMS). This study was undertaken to determine whether hormonal changes during the menstrual cycle influence pregnanolone pharmacokinetics and to compare PMS diagnosis-related differences in pregnanolone pharmacokinetics. Methods: Seven patients with premenstrual syndrome and seven female controls were given three increasing doses of pregnanolone in the follicular and luteal phase of the menstrual cycle. Results: Mean pregnanolone elimination half-life varied between 28.4 min and 31.8 min and clearance between 59.6 ml · min⁻¹ · kg⁻¹ and 64.0 ml · min⁻¹ · kg⁻¹, depending on diagnostic group and cycle phase. No significant differences in pregnanolone pharmacokinetic properties were found between PMS patients and controls in either phase of the menstrual cycle. Furthermore, no differences in pharmacokinetic variables were detected between cycle phases. Conclusion: Pregnanolone pharmacokinetics do not differ between follicular and luteal phase of the menstrual cycle, nor between PMS patients and control subjects. Received: 16 September 1998 / Accepted in revised form: 27 November 1998     

Single-dose pharmacokinetics of paracetamol and its conjugates in Chinese non-insulin-dependent diabetic patients with renal impairment

Objective: A single oral dose of paracetamol (20 mg · kg⁻¹) was given to 38 Chinese patients with non-insulin-dependent diabetes mellitus (NIDDM) who had either normal renal function or varying degrees of renal impairment, with creatinine clearances ranging from 4 to 123 ml · min⁻¹ · 1.73 m⁻². The plasma and urinary concentrations of paracetamol and its major metabolites were measured by high-performance liquid chromatography (HPLC). Results: The absorption and elimination of paracetamol were unaffected by renal impairment. However, the area under the plasma concentration time curve and the elimination half-life of paracetamol metabolites increased significantly with worsening renal insufficiency. Mean renal clearances of paracetamol and its conjugates were significantly reduced in these subjects. There was no evidence of altered metabolic activation with renal impairment. Conclusion: The results demonstrate that paracetamol disposition is minimally affected by diabetic nephropathy; however, extensive accumulation of conjugates may occur. Received: 2 September 1996 / Accepted in revised form: 11 December 1996