A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients

Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml^–1, C_max was 832 vs 871 ng⋅ml^–1 and t_max was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely. Received: 19 October 1995/Accepted in revised form: 8 January 1996     

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers

Objective: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. Results: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC_0–∞12.6 μg ⋅ h ⋅ ml⁻¹) in comparison with healthy volunteers (AUC_0–∞39.3 μg ⋅ h ⋅ ml⁻¹). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free C_max (5.0 vs. 2.6 ng/ml) but similar free AUC_0–∞(0.13 vs. 0.11 μg ⋅ h ⋅ ml⁻¹) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemo- dialysis. Conclusion: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound non-steroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free C_max value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable. Received: 22 January 1996/Accepted in revised form: 19 June 1996     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

Comparison of the pharmacokinetics of tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis

Objective: The pharmacokinetics of tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg ⋅kg⁻¹ tirilazad mesylate over 10 min. Results: Mean tirilazad AUC_0–∞ was 8.83 μmol h⋅l⁻¹ and 18.6 μmol h⋅l⁻¹ in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l⋅h⁻¹) was approximately 2.1 fold lower than in healthy volunteers (27.8 l⋅h⁻¹). The differences were statistically significant. Mean U-89678 AUC_0–∞ in cirrhotic subjects (3.88 μmol h⋅l⁻¹) was 2.5 fold higher than in healthy controls (1.53 μmol h⋅l⁻¹), but the difference was marginally significant. Conclusion: These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment. Received: 10 August 1995/Accepted in revised form: 10 July 1995     

Influence of repeated oral doses of ethinyloestradiol on the metabolic disposition of [13C2]-ethinyloestradiol in young women

Objective: To examine the influence of daily oral administration of ethinyloestradiol on the total clearance of ¹³C-labeled ethinyloestradiol in women. Methods: 19, healthy, young women received a single IV dose of 0.06 mg ¹³C-ethinyloestradiol. Subsequently, they were treated with daily oral doses of 0.06 mg ethinyloestradiol for 8 days. On the last day of oral treatment, they received a further IV dose of 0.06 mg ¹³C-ethinyloestradiol. The pharmacokinetic parameters clearance, area under the serum level-time curve, terminal half-life, steady-state volume of distribution and mean residence time of ¹³C-ethinyloestradiol in each volunteer were evaluated after both IV doses, and the corresponding pairs of parameters were examined statistically for the significance of intraindividual differences. Results: Following the first (second) intravenous administration, the mean area under the curve was 2.54 (2.67) ng⋅h⋅ml⁻¹. The terminal half-life and mean residence time were 9.7 (9.6) h and 10.5 (10.1) h, respectively. The steady-state volume of distribution was 4.3 (3.9) l⋅kg⁻¹ and the clearance was 7.0 (6.6) ml⋅ min⁻¹⋅kg⁻¹. No significant difference was observed in any of these parameters between the first and the second IV doses of ¹³C-EE₂. Conclusions: Since the clearance in particular remained unchanged after repeated oral administration of ethinyloetradiol, the hypothesis that ethinyloestradiol can inhibit its own metabolism in vivo can be rejected. Received: 25 July 1995/Accepted in revised form: 27 November 1995     

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     

Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide

Objective: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. Methods: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. Results: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(0–t), the study showed a mean value of moexipril 437 ng ⋅ ml⁻¹⋅ h⁻¹ following administration of moexipril alone and 416 ng ⋅ ml⁻¹⋅ h⁻¹ following moexipril concomitantly with hydrochloro- thiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng ⋅ ml⁻¹⋅ h⁻¹, respectively. The c_max of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng ⋅ ml⁻¹ after administration of moexipril alone and 241.0 (69.2) ng ⋅ ml⁻¹ after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) μg. Conclusion: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide. Received: 10 July 1995/Accepted in revised form: 3 March 1996     

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy

Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (C_max = 452.2 ng ⋅ ml⁻¹, t_max = 2.3 h, AUC = 26 μg ⋅ ml⁻¹⋅ h, t_1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml⁻¹) and Day 5 (70.6 ng ⋅ ml⁻¹), and mean t_1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics. Received: 2 January 1995/Accepted in revised form: 1 April 1996     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zopiclone

Objective: We studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. Methods: A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 h. Results: Itraconazole significantly increased the C_max of zopiclone from 49 to 63 ng ⋅ ml⁻¹. The t_1/2 of zopiclone was prolonged from 5.0 to 7.0 h. The AUC(0–∞) of zopiclone was increased from 415 to 719 ng ⋅ ml⁻¹ h by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Conclusion: Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults. Received: 15 April 1996 /Accepted in revised form: 4 June 1996     

Haemodynamic effects and pharmacokinetics of oral d-and l-nebivolol in hypertensive patients

Objective: Nebivolol is a selective β₁-adrenergic receptor blocker possessing an ancillary vasodilating effect. The objective of the present study was to study the haemodynamic and pharmacokinetic properties of nebivolol 5 mg once daily in a double-blind, placebo-controlled cross-over study. Methods: Fifteen patients, 12 men and 3 women, with essential hypertension were investigated. Blood pressure and peripheral circulation were determined after acute oral nebivolol administration, 5 mg daily, and after 4 weeks treatment. Results: The acute effect on blood pressure upon single-dosing was weak and non-significant. After 4 weeks both systolic blood pressure (152 vs 163 mmHg) and diastolic blood pressure (89 vs 97 mmHg) were significantly reduced after nebivolol treatment as compared to placebo. Following the first dose the venous volume was higher on placebo (5.88 ml ⋅ 100 ml⁻¹ tissue) as compared to active nebivolol treatment (5.17 ml ⋅ 100 ml⁻¹ tissue), while there were no statistically significant differences with regard to venous plethysmographic findings after 1 month on placebo (5.53 ml ⋅ 100 ml⁻¹ tissue) or on active treatment (5.97 ml ⋅ 100 ml⁻¹ tissue). Calculated peripheral resistance did not differ between active treatment (617 units) or placebo (548 units) after the first dose, whereas it was significantly lowered after 4 weeks of nebivolol treatment (483 units) as compared to placebo (593 units). Conclusions: Oral nebivolol 5 mg once daily lowered blood pressure and heart rate during steady state compared to placebo. Moreover, venous volume was reduced during acute but not steady-state dosing, while peripheral resistance was unaffected in the acute phase but reduced during steady state. Plasma concentrations of the separate enantiomers plus hydroxylated metabolites after the first and last dose in hypertensive patients were similar to those in healthy subjects. Received: 1 March 1996/Accepted in revised form: 2 July 1996     

Variability in the plasma protein binding of velnacrine (1-hydroxy tacrine hydrochloride) A potential agent for Alzheimer’s disease

Objectives: To quantify the protein binding of velnacrine in healthy individuals and investigate potential sources of variability. Setting: Medical School Unit, Southmead Hospital, Bristol. Subjects: Plasma samples were obtained from the following groups: a) 11 healthy volunteers aged 18 to 30 years; b) 10 healthy volunteers aged 73 to 87 years; c) 10 patients aged 65 to 85 years hospitalised for a variety of acute illnesses. Methods: Aliquots of plasma from the above subjects were incubated with various concentrations of velnacrine, in the presence and absence of tacrine hydrochloride. Standard solutions of human serum albumin and α₁ acid glycoprotein were incubated with velnacrine. The degree of protein binding was determined using the Amicon centrifree micropartition system. Results:Over the range of concentrations from 10 to 320 ng ⋅ml⁻¹, there was a decrease in protein binding from 59.1 to 46.7%. 2) At 40 ng⋅ml⁻¹ the plasma protein binding of velnacrine was 54.8% in the group a subjects, 51.9% in the group b subjects and 53.0% in the group c subjects (NS). 3) The mean total plasma protein concentration was significantly lower in the samples from elderly subjects. The mean albumin and α₁ acid glycoprotein concentrations were lower and higher respectively in patients with acute disease. 4) Velnacrine was shown to bind to both albumin and α₁-acid glycoprotein, but together they did not account for total binding. 5) The binding of velnacrine was significantly decreased from 59.3 to 43.9% in the presence of a therapeutic concentration (25 ng ⋅ml⁻¹) of THA. There was no evidence that velnacrine displaced THA. Conclusion: Protein binding can be discounted as a major source of variation in the relationship between drug concentration and effect. Received: 23 March 1995/Accepted in revised form: 14 June 1995     

Effect of rifampicin on the pharmacokinetics of itraconazole in normal volunteers and AIDS patients

Objective: To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans. Methods: Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole concentration was 16 ng · ml^–1. Results: Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC_0–24 was 3.28 vs 0.39 μg · h · ml⁻¹ in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC_0–24 was 1.07 vs 0.38 μg · h · ml^–1 in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC_0–24 of itraconazole in phase 2 was approximately 64% compared with phase 1. Conclusion: Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered concomitantly. Received: 2 September 1997/Accepted in revised form: 16 December 1997     

Concentration-effect relationship of the positive chronotropic and hypokalaemic effects of fenoterol in healthy women of childbearing age

Objective: To analyse fenoterol-induced tachycardia and hypokalaemia, the most important and most frequent adverse effects of tocolytic therapy with β₂-adrenoceptor agonists in females of childbearing age. Methods: The study was performed as a double blind, randomised, placebo controlled, cross over trial. Seven healthy women aged 22–38 y, received intravenous infusions of fenoterol at 3 different rates within the therapeutic range for tocolysis (0.5,1.0, and 2.0 μg⋅min⁻¹) and placebo. The time courses of the plasma concentrations of fenoterol and potassium, and the heart rate were analysed with mixed effects pharmacokinetic-pharmacodynamic (PKPD) modeling using NONMEM. Results: The plasma concentration-time course followed a linear two compartment model. Fenoterol-induced tachycardia was described by a linear concentration-effect model with baseline. The estimated baseline and slope parameters were 78 beats⋅min⁻¹ and 0.032 beats⋅min⁻¹⋅μg⁻¹⋅l, respectively. Fenoterol-induced hypokalaemia could be described by a physiological indirect response model including feedback; the Estimated basal plasma potassium concentration was 3.93 mmol⋅l⁻¹ and the slope factor for the fenoterol-induced relative increase in the efflux of potassium from the extracellular space was 6.22^*10⁻⁴ ng⋅l⁻¹. Conclusion: The estimated population parameters permitted calculation of the expected time course of tachycardia and hypokalaemia in women after the initiation of tocolysis with fenoterol over the clinically relevant concentration range, and prediction of its variability. Based on simulation, our model predicted that a continous infusion of 2.0 μg⋅min⁻¹ (highest rate examined) would increase heart rate to 113 beats⋅min⁻¹ at steady state and lower the plasma potassium concentration to 2.77 mmol⋅l⁻¹ 1.5 h after beginning the infusion. Thereafter, the plasma potassium concentration would slowly return to normal. Received: 7 December 1995/Accepted in revised form: 29 April 1996     

A drug interaction study between cicletanine and tolbutamide in healthy volunteers

Objective: To determine the possible interaction between the antihypertensive agent cicletanine and the hypoglycaemic drug tolbutamide. Methods: Time-courses of glycaemia and serum immunoreactive insulin (IRI) were followed in 10 healthy subjects after two tolbutamide infusions in each volunteer: initially alone and 9 days later concomitantly with repeated oral cicletanine. Any drug interaction was quantified on the basis of a decrease or increase in the AUC with time of glycaemia and IRI by subtraction of baseline concentration (AUC₀ ²⁴⁰-GLY and AUC₀ ⁶⁰-IRI). Peak glycaemia and peak IRI, and the corresponding time to peaks, were also assessed. Results: Following tolbutamide, mean AUC₀ ²⁴⁰-GLY values were 97.7 and 98.8 mmol⋅l⁻¹⋅min, without or with cicletanine, respectively; the corresponding AUC₀ ⁶⁰-IRI were 485 and 321 mU⋅l⁻¹⋅min. Mean peak glycaemia values were 0.996 and 1.071 mmol⋅l⁻¹. Regarding the peak IRI, a decrease was observed after tolbutamide and cicletanine: median values were 29.2 and 17.4 mU⋅l⁻¹. The corresponding median time to peak of glycaemia and IRI values were 30 and 30 min, and 5 (all subjects) and 5 min. Conclusion: No clinically relevant interaction was shown after the concomitant administration of repeated oral doses of cicletanine and acute intravenous tolbutamide to healthy volunteers. Received: 28 June 1995/Accepted in revised form: 7 November 1995     

Pharmacokinetics of flosequinan in patients with heart failure

Objective: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure. Results: After a single dose of 100 mg, C_max of the parent compound (2.52 mg ⋅ l⁻¹) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (C_max 8.4 vs 3.21 mg ⋅ l⁻¹). No adverse effects were observed. Conclusion: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity. Received: 16 January 1995/Accepted in revised form: 30 October 1995     

Absorption rate of methylxanthines following capsules,cola and chocolate

Objective: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. Methods: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. Results: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (C_max: 1.93 μg ⋅ ml⁻¹); and 2 (C_max: 2.05 μg ⋅ ml⁻¹). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5–2.0 h after treatment (For cola, C_max: 1.57 μg ⋅ ml⁻¹); and for chocolate, C_max: 1.50 μg ⋅ ml⁻¹. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (C_max: 6.72 μg ⋅ ml⁻¹). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (C_max: 8.05 μg ⋅ ml⁻¹). Conclusions: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject. Received: 6 December 1995/Accepted in revised form: 6 July 1996     

Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone – a novel antiarrhythmic agent

Objective: The present study was done to investigate the effect of food on the bioavailability of diprafenone. Methods: The most important pharmacokinetic parameters (C_max, t_1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart. The serum concentrations of diprafenone and its hydroxy-metabolite were determined up to 24 hours after administration by a sensitive, specific HPLC method. Fifteen healthy, male volunteers were enrolled in the trial. Their mean height, weight and age were 183 cm, 80 kg and 22 years, respectively. Fourteen volunteers were found to be rapid hydroxylators and one was a slow hydroxylator of debrisoquine. Only data from the rapid hydroxylators were used in the statistical analysis. Results: Food increased the oral bioavailability of diprafenone by approximately 50%. This effect was similar in rapid and in slow hydroxylators. The only slow hydroxylator in this trial had an AUC_0–last ratio (with food/fasting) of 1.54. These findings suggest that diprafenone should be administered in a constant temporal relationship to food. Received: 24 July 1995/Accepted in revised form: 4 January 1996     

Absolute bioavailability of fluoride from disodium monofluorophosphate and enteric-coated sodium fluoride tablets

Objectives: The absolute bioavailability and other pharmacokinetic parameters of two fluoride formulations were investigated in 13 healthy volunteers, aged 61–70 years. Methods: The following formulations were administered, under fasting conditions, in a single-dose three-way cross-over design: tablets of 76 mg disodium monofluoro phosphate (MFP, equivalent to 10.0 mg F⁻ ion), enteric-coated (e.c.) tablets of 25 mg sodium fluoride (NaF_or, equivalent of 11.3 mg F⁻ ion), and an isoosmotic aqueous injection solution (4 ml) of 22.1 mg sodium fluoride (NaF_iv, equivalent of 10.0 mg F⁻ ion). There was a wash-out period of at least one week between each administration. Blood was sampled before and during a 24-hour period after administration. For F⁻ excretion urine was sampled 48 hours before (baseline) and over the 48 hours after the adminstration. Results: The mean t_1/2 values of the three formulations were 8.3, 8.7 and 8.3 h for MFP, NaF_or and NaF_iv respectively, and were not significant different. Mean C_max after MFP was significantly higher than after NaF_or [344 vs 142 μg⋅l⁻¹]. Mean t_max for MFP was shorter than for NaF_or [1.1 vs 4.6 h]. MFP had significantly higher bioavailability [102.8%] than NaF_or [64.2%]. Conclusion: The MFP formulation showed higher bioavailability with smaller variation than the NaF_or formulation. MFP is preferable, therefore, for fluoride therapy in clinical practice, and changing from NaF_or to MFP will require adjustment of the dose. Received: 23 May 1995/Accepted in revised form: 8 January 1996     

Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function

Background: Glibenclamide (Gb) may provoke long-lasting hypoglycaemic reactions, and one of the known risk factors is impaired renal function. We have demonstrated Gb to have a terminal elimination half-life of 15 h, and the main metabolites have a hypoglycaemic effect. With few exceptions, detailed studies on second generation sulphonylureas in diabetics with impaired renal function are lacking. Therefore, we analysed the pharmacokinetics of Gb and its active metabolites, 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxyglibenclamide (M2) in this patient group. Methods: Two groups of 11 diabetic patients with impaired renal function (IRF, iohexol clearance range 7–42 ml · min⁻¹ · 1.73 m⁻²) or normal renal function (NRF, iohexol clearance range 75–140 ml · min⁻¹ · 1.73 m⁻²) were compared. A single oral 7-mg dose of Gb was administered after overnight fasting. Serum samples and urine collections were obtained over 48 h and 24 h, respectively. Concentrations of Gb, M1 and M2 were determined by a sensitive and selective high-performance liquid chromatography assay. Results: Peak serum values of M1 (24–85 ng · ml⁻¹ vs 16–57 ng · ml⁻¹), M2 (7–22 ng · ml⁻¹ vs <5–18 ng · ml⁻¹) and M1 + M2 (32–100 ng · ml⁻¹ vs 23–76 ng · ml⁻¹) were higher in the IRF group. AUC and C_max of Gb were lower and the clearance to bioavailability ratio (CL/f) was higher in the IRF group. AUC and C_max of M1 were higher and CL/f lower in the IRF group. Much lower amounts of M1 and M2 were excreted in the urine in the IRF group (7.2% vs 26.4% in 24 h). The fraction of the Gb dose excreted as metabolites (fe(met) 0–24 h), ranged between 0.005 and 0.36 and correlated significantly with renal function measured by iohexol clearance. No other pharmacokinetic differences were found. Conclusion: The differences in AUC, C_max and CL/f of Gb may be explained by a higher free fraction in the IRF group which would increase Gb metabolic clearance. The inverse findings regarding M1 may be explained by the fact that the metabolites are primarily eliminated by the kidneys. After a single dose of Gb, neither Gb, M1 nor M2 seemed to accumulate in diabetic subjects with IRF. As only small amounts of M1 and M2 were excreted in the urine, this indicates one or several complementary non-renal elimination routes, e.g. shunting of metabolised Gb to the biliary excretion route and/or enterohepatic recycling of both metabolites and unmetabolised Gb. Received: 21 April 1997 / Accepted in revised form: 14 October 1997     

Multiple dose pharmacokinetics of tiludronate in healthy volunteers

Objectives: A double-blind, placebo-controlled study was conducted to assess the pharmacokinetics and pharmacodynamics of the bisphosphonate tiludronic acid, administered once daily as sodium tiludronate 200, 400, 600 and 800 mg for 12 days. Four groups of ten subjects participated in the study, with a drug to placebo ratio of 4:1. Methods: Pre-dose blood samples were taken on alternate days, starting on Day 1 and additional samples were collected over 144 h following the final dose on Day 12. Urine was collected over 24 h after the final dose. Indices of calcium homeostasis and biochemical markers of bone turnover were assessed during the study as pharmacodynamic parameters. Tolerability was evaluated with special emphasis on renal function and gastrointestinal irritation. Adverse experiences were assessed at regular time intervals. Results and conclusions: Steady state was attained from Day 4 (200 mg) or from Day 6 (400, 600 and 800 mg). Following the final dose on Day 12, minimal plasma concentrations (C_min) ranged between 0.19 and 1.5 mg ⋅ l⁻¹, and maximal plasma concentrations (C_max) between 1.1 and 7.8 mg⋅l⁻¹ for the lowest and highest doses, respectively. A supra-proportional increase in C_max, AUC₂₄ and A^e ₂₄ with dose was observed. There was a linear relationship between the plasma tiludronic acid and its urinary excretion rate, so, the disproportional rise in C_max and AUC₂₄ with increasing dose could not be attributed to saturation of renal excretion. Certain indices of calcium homeostasis changed significantly during the study, but generally, became only prominent at the highest dose level of 800 mg. Total serum calcium and the urinary calcium/creatinine clearance ratio fell, indicating depression of osteoclastic bone resorption, which was not revealed by serum osteocalcin levels probably because of the brevity of the treatment (12 days). In response to the decline in serum calcium, serum 1,25-dihydroxyvitamin D₃ and intact PTH (1–84) levels increased. None of the safety parameters raised any concerns about the safety of sodium tiludronate administered in this way. Received: 11 September 1995/Accepted in revised form: 28 March 1996