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     

Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man

Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 g dDAVP. For intestinal administration 400 g dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA.Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min^–1·kg^–1, amount excreted in urine 2.0 g and renal clearance was 0.8 ml·min^–1·kg^–1.The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions.The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.     

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     

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 and absolute bioavailability of lansoprazole

Objective: In a crossover study 12 healthy volunteers received lansoprazole 15 mg or 30 mg orally, or 15 mg intravenously in randomized order as a single dose. Blood samples were taken and plasma levels of lansoprazole were determined using an HPLC method. The volunteers were phenotyped for the debrisoquine/sparteine and mephenytoin polymorphisms. Results: The total clearance was 517 ml⋅min⁻¹, and the absolute bioavailability was 91% for the 30-mg and 81% for the 15-mg enteric-coated formulation. The elimination half-life was about 1 h. No correlation of the plasma levels to the sparteine metabolic ratio was found, and no correlation to the mephenytoin type could be established, since all volunteers of the mephenytoin type were extensive metabolizers. Although considerable variation, inter- and intraindividually, was observed, the increase in c_max and AUC did not deviate from dose proportionality. The present galenic formulation ensures a high bioavailability after a single dose. Received: 24 March 1995/Accepted in revised form: 11 July 1995     

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     

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     

Influence of renal failure on cytochrome P450 activity in hypertensive patients using a “cocktail” of antipyrine and nifedipine

Objective. Two substrates were coadministered in a “cocktail” approach to evaluate the contribution of renal failure to drug oxidation. Patients. Nineteen hypertensive patients, nine of them with chronic renal failure (CL_CR 38.9 vs 102.3 ml⋅min⁻¹⋅1.73 m⁻²), were investigated after peroral administration of a combination of antipyrine (500 mg, in capsules) and nifedipine (10 mg, in Oxcord capsules) in the morning after an overnight fast. Results. This “cocktail” approach made it possible to characterize in vivo the activities of different forms of cytochrome P₄₅₀ in a single-study protocol using the total clearance of nifedipine and clearance for production of 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine (OHA) and norantipyrine (NORA). With this “cocktail” approach (antipyrine plus nifedipine), we can suggest a selective effect on the activities of cytochrome P₄₅₀ forms associated with the formation of dehydronifedipine (P₄₅₀ III A₄) and of NORA in patients with mild renal failure under long-term antihypertensive therapy. Received: 12 July 1994 /Accepted in revised form: 7 October 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     

Effect of diprafenone on the pharmacokinetics of digoxin

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 × 1 mg) or digoxin and diprafenone (3 × 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng ⋅ml⁻¹], AUC_0–24 values [41 (7) vs 48 (9) ng⋅h⋅ml⁻¹ and C_ss-max [3.9 (0.6) vs 5.5 (0.9) ng⋅ml⁻¹]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng⋅ml⁻¹, 39 (11) ng⋅h⋅ml⁻¹, and 3.9 (1.1) ng⋅ml⁻¹ for trough concentration, AUC_0–24 and C_max respectively]. The mean relative magnitude of the increase in AUC_0–24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and C_ss was caused by reduced renal clearance of digoxin. Received: 10 July 1995 /Accepted in revised form: 5 October 1995     

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     

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     

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     

Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam

Objective: The effect of short-term heat exposure in a Finnish sauna on hepatic first-pass metabolism and the capacity to metabolize midazolam were studied in a crossover trial. Midazolam oral (15 mg) and intravenous (0.05 mg ⋅ kg⁻¹) was given to 6 healthy young male volunteers, in random order, during a control session and a sauna bathing session (temperature 85–100° C, relative humidity 25–30%). Blood samples for the determination of plasma midazolam and α-hydroxy midazolam concentrations were taken for 6 h after drug administration. Results: After oral administration, the bioavailability and clearance of midazolam were not affected by sauna bathing, nor was there a significant difference in α-hydroxy midazolam plasma concentration or the α-hydroxy midazolam/midazolam AUC-ratio between the sessions. Midazolam C_max was increased and its t_1/2β was prolonged during the sauna session, but the clinical relevance of the findings appears to be modest. The pharmacokinetics of intravenous midazolam were not affected by sauna bathing. Conclusions: Short-term heat exposure may not affect the first-pass metabolism or hepatic capacity to metabolize midazolam. Received: 23 October 1995 /Accepted in revised form: 22 May 1996     

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     

Comparison of dose requirement,serum erythropoietin and blood pressure following intravenous and subcutaneous erythropoietin treatment of dialysis patients IV and SC erythropoietin

Objective: The purpose of the study was to investigate the effect of route of administration of erythropoietin (EPO) on the dose requirement in dialysis patients after intravenous (IV) and subcutaneous (SC) therapy. Methods: The study was performed as a single centre, prospective, open, combined parallel and cross-over study of 50 dialysis patients, consecutively randomised to IV or SC treatment with EPO. The initial dose was 40 U⋅kg⁻¹ 3-times weekly, adjusted to increase haemoglobin (Hgb) from a median 5.3 mmol⋅l⁻¹ to a target of haemoglobin 6.5–7.5 mmol⋅l⁻¹. After reaching the target level, the haemoglobin was maintained for 4 months (Period 1). Then IV and SC treatment was switched for a further 4 months (Period 2). The study included high risk patients. The adjustment period was completed by 38 patients, Period one by 32 patients (IV/SC = 15/17; male/female = 19/13; age = 54 (24– 71) y), and Period two by 22 patients. Results: No significant difference was found between the two groups in the reticulocyte response, the rate of Hgb increase (IV 0.7 versus SC 0.5, mmol⋅l⁻¹⋅ month⁻¹), time to reach target level (IV 43 versus SC 60 days), or total EPO dose per increase in haemoglobin to target level (IV 663 versus SC 946 (U⋅kg⁻¹) per (mmol Hgb⋅l⁻¹). The overall median maintenance dose during the last month of the two four month periods was 105 (range IV 51–336) U⋅kg⁻¹⋅w⁻¹ and SC 104 (range 21–321) U⋅kg⁻¹⋅w⁻¹. Trough serum EPO levels were significantly higher during SC treatment. The blood pressure did not change significantly from the base level after either route of administration; start 133/80 versus 143/80 mmHg, target 127/78 versus 154/85 mmHg, and maintenance period 140/84 versus 142/85 mmHg. Thus, three-times weekly IV or SC EPO did not differ significantly in efficacy or in the effect on blood pressure in dialysis patients. Received: 13 June 1995/Accepted in revised form: 30 October 1995     

Effect of moderate or severe liver dysfunction on the pharmacokinetics of γ-hydroxybutyric acid

Objectives: To assess the effect of moderate or severe liver dysfunction on the pharmacokinetics of γ-hydroxybutyric acid (GHB). Methods: The absorption and disposition kinetics of GHB were studied in eight cirrhotic patients without ascites (Child’s class A) and eight cirrhotic patients with ascites (Child’s class C), after administration of a single oral dose of 25 mg⋅kg⁻¹. The liver metabolic function of each patient was evaluated by measuring antipyrine clearance and the formation rate of the lidocaine metabolite monoethylglycinexylidide (MEGX). Results: Compared to those previously determined in eight healthy control subjects given the same GHB dose, mean AUC values were double or greater in the cirrhotic patients. Accordingly, apparent oral clearance was markedly reduced (from 9.1 to 4.5 and 4.1 ml⋅min⁻¹⋅kg⁻¹ in nonascitic and ascitic patients, respectively). Terminal half-life (t_1/2), was significantly longer in nonascitic patients than in control subjects (32 vs 22 min). A further significant prolongation of t_1/2, most likely due to an increased distribution volume, was observed in patients with ascites (56 min). Nonetheless, GHB plasma concentrations fell to either undetectable or negligible levels by the end of the usual dosing intervals (6–8 h). More limited changes were noted in the absorption parameters. The peak level (C_max) increased only in nonascitic patients, but not proportionally to the increase in AUC. The time to C_max increased from 30 to 45 min in both cirrhotic groups. These findings are consistent with a slowed rate of GHB absorption in cirrhotic patients. Adverse effects were similar, for intensity and duration, to those recorded in healthy volunteers, i.e., mild and transient. Conclusions: Although liver cirrhosis causes significant modifications of GHB disposition kinetics, the increase in t_1/2 is not such as to cause drug accumulation on repetitive dosing. However, in consideration of the higher mean plasma levels observed in cirrhotic patients, it appears wise to keep the initial GHB daily dose at the lower end of the therapeutic range and to carefully monitor the patients if upward dose adjustments are required. Received: 27 July 1995/Accepted in revised form: 24 November 1995     

The effect of hypoxaemia on drug disposition in chronic respiratory failure

Objective: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure. Methods: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods. Results: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO₂ ≤ 50 Torr) was not significantly different from the value during normoxaemia (PaO₂ ≥ 60 Torr) [76.9 and 62.4 ml ⋅ min⁻¹]. The volume of distribution was not affected by acute hypoxaemia (121 ml ⋅ kg⁻¹ without and 109 ml ⋅ kg⁻¹ with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml ⋅ min⁻¹, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml ⋅ min⁻¹). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.     

Differences in the response of serum lipoproteins to fenofibrate between women and men with primary hypercholesterolaemia

Objective: We studied possible sex differences of the effect of fenofibrate on serum lipoproteins. Twenty-three patients with primary hypercholesterolaemia (10 postmenopausal women and 13 aged-matched men) were treated with slow-release fenofibrate for 96 weeks. Results: Steady state lipoprotein concentrations were reached after 12 and 24 weeks of treatment in women and men, respectively. During the subsequent follow-up the lipoprotein concentrations remained constant. In women total and low-density lipoprotein (LDL) cholesterol decreased from 299 to 234 mg⋅dl⁻¹ and from 210 to 151 mg⋅dl⁻¹, respectively, and in men from 265 to 233 mg⋅dl⁻¹ and from 192 to 160 mg⋅dl⁻¹. The decrease in triglycerides was also more pronounced in women (−42%) than in men (−18%). High-density lipoprotein (HDL) cholesterol increased significantly in women from 53 to 63 mg⋅dl⁻¹ but not in men (45 to 50 mg⋅dl⁻¹). Since the changes in LDL and HDL cholesterol occurred in opposite directions, the decrease in LDL/HDL cholesterol ratio was accentuated in both groups. However, this ratio was decreased almost twofold in women (−41%) compared to men (−23%). Although the serum concentrations of fenofibric acid were 1.3-fold higher in women than in men, which was probably due to the higher body weight in men (1.2-fold), this difference can hardly explain the favorable effect on lipoproteins in women. Conclusion: The present study indicates that fenofibrate might be very effective by reducing the concentrations of atherogenic lipoproteins in postmenopausal women. Received: 28 July 1995/Accepted in revised form: 20 November 1995     

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