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     

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     

Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease

Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.) dose of theophylline, both in patients with idiopathic Parkinson's disease (PD). Methods: Pharmacokinetic parameters (AUC and C_max) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in 12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at doses of up to 300 mg b.i.d. The parameters AUC, C_max and t_max for ropinirole were compared before, during and after oral theophylline co-treatment. Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and without ropinirole: 68.6 μg · h⁻¹ · ml⁻¹ and 70.0 μ· h⁻¹ · ml⁻¹, respectively; mean C_max with and without ropinirole: 11.07 μ g · ml⁻¹ and 11.83 μg · ml⁻¹, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h⁻¹ · ml⁻¹ and 22.09 ng · h⁻¹ · ml⁻¹, respectively; mean C_max for ropinirole with and without theophylline: 5.65 ng · ml⁻¹ and 5.54 ng · ml⁻¹, respectively; median t_max for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively). Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses. Received: 10 August 1998 / Accepted in revised form: 27 January 1999     

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

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

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     

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     

Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes

Objective: Interindividual variations in immunoreactivity and function of three major human drug metabolising P450 monooxygenases has been investigated in liver microsomes from 42 Caucasians (kidney donors or liver biopsies). Methods: Diclofenac 4′-hydroxylation, dextromethorphan O-demethylation and midazolam 1′-hydroxylation, measured by HPLC in incubates, were used as probes to determine CYP2C9, CYP2D6 and CYP3A4 function kinetics, respectively. Immunoquantification of the three isoforms was achieved by Western blotting, using rabbit polyclonal antibodies raised against human CYP2C9 and human CYP3A4, and mouse monoclonal antibody raised against human CYP2D6. Results: Diclofenac 4′-hydroxylation exhibited Michaelis-Menten kinetics with k_M= 3.4 μmol ⋅l⁻¹ and V_max = 45 nmole ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2C9 was correlated with V_max and CL_int. Dextromethorphan O-demethylation in EM (extensive metabolisers) liver microsomes also showed Michaelis-Menten kinetics, with k_M = 4.4 μmol ⋅l⁻¹ and V_max = 5.0 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2D6 was correlated with V_max and CL_int. Midazolam 1′-hydroxylation also exhibited Michaelis-Menten kinetics with k_M = 3.3 μmol ⋅l⁻¹ and V_max = 35 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP3A4 was correlated with V_max and CL_int. Immunoreactivity and function were correlated for each isozyme, but there was no cross correlation between isozymes. Conclusion: The velocity of metabolite formation (V_max) by the three major human drug metabolising P450 monooxygenases is correlated with their immunoreactivity in liver microsomes. Interindividual variation was much larger for V_max than k_M. Interindividual variability was more pronounced for CYP2D6, probably due to the presence of several different functional alleles in the population of extensive metabolisers. Received: 27 December 1995/Accepted in revised form: 29 March 1996     

Food increases the bioavailability of mefloquine

Objectives: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy volunteers. Methods: In an open, two-way cross-over study, 20 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of 750 mg mefloquine in the absence or presence of a standardised, high-fat breakfast, administered 30 min before drug administration. Blood samples were taken at specific times over an 8-week period. Plasma concentrations of mefloquine and its carboxylic acid metabolite were determined by high-performance liquid chromatography for pharmacokinetic evaluation. Results: The parameters C_max and AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher under post-prandial conditions than under fasting conditions (mefloquine: mean C_max 1500 vs 868 μg · l⁻¹, mean AUC 645 vs 461 mg l⁻¹ · h; metabolite: C_max 1662 vs 1231 μg · l⁻¹, AUC 1740 vs 1310 mg l⁻¹ · h). The intersubject variability in C_max and AUC of mefloquine was less than 30% (coefficient of variation). The time to peak plasma concentration of mefloquine was significantly shorter after food intake (17 vs 36 h). Compared with absorption in volunteers who had fasted, food did not alter t_1/2 (mefloquine and its metabolite) and t_max (metabolite). Conclusion: Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible. Received: 10 February 1997 / Accepted in revised form: 16 June 1997     

Lack of a kinetic interaction between fluconazole and mexiletine

Objective. To investigate the effect of fluconazole on the kinetics of mexiletine. Methods. Six healthy male volunteers participated in a crossover study. On the 1st day, the subjects received 200 mg mexiletine alone. On days 2–7 they received 200 mg fluconazole orally, and on day 8 they received 200 mg mexiletine and 200 mg fluconazole concomitantly. In a third phase two subjects received 400 mg fluconazole daily. Results. No differences in concentrations were observed between the three phases. The area under the concentration curves (AUC) after administration of mexiletine alone and in combination with fluconazole 200 mg/day were 6.63 and 7.31 μg ⋅ h ⋅ ml⁻¹, respectively. Conclusion. These findings suggest that fluconazole does not inhibit mexiletine metabolism. Received: 7 July 1995/Accepted in revised form: 19 September 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     

Influence of an acidic beverage (Coca-Cola) on the absorption of itraconazole

Objective: To evaluate the effectiveness of Coca-Cola in enhancing the absorption of itraconazole. Methods: Eight healthy volunteers were randomized to receive two treatment sequences in a two-way crossover design with a 1-week wash-out period separating each study treatment. Treatment I, the control, consisted of 100 mg itraconazole with 325 ml water. Treatment II was identical to treatment I, except that itraconazole was administered with 325 ml of Coca-Cola (pH 2.5). Results: Serum itraconazole concentrations, after administration with Coca-Cola (treatment II), were higher than after administration with water (treatment I). The mean AUC was 1.12 vs 2.02 μg · h · ml⁻¹, the mean C_max was 0.14 vs 0.31 μg · ml⁻¹and the mean t_max was 2.56 vs 3.38 h in treatments I and II, respectively. Conclusion: The absorption of itraconazole can be enhanced by Coca-Cola. Received: 4 November 1996 / Accepted in revised form: 21 January 1997     

Pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure elevation

Objective: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug. Methods: We studied 17 patients with transient IOP elevation, who were given 62.5–500 mg acetazolamide orally as single or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. Results: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation, as follows: 0.0468 · CCR l · h⁻¹. The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 l · kg⁻¹, 0.821 · h⁻¹, and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an E_max model. The maximal effect in lowering the IOP (E_max) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC₅₀) was 1.64 μg · ml⁻¹. As 70% of E_max was achieved at a plasma concentration of 4 μg · ml⁻¹, this concentration was considered satisfactory for lowering IOP. The recommended dosage was calculated so that the minimum plasma concentration at steady state exceeded this target concentration; 250 mg t.i.d., 125 mg t.i.d., 125 mg b.i.d., and 125 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml · min⁻¹, respectively. Conclusion: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient rises in IOP following intraocular surgery. Received: 10 April 1997 / Accepted in revised form: 21 October 1997     

Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humour of patients by different topical application modes

Objectives: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humour. Methods: Two hundred and twenty-four patients undergoing cataract extraction received 0.3% ciprofloxacin, norfloxacin or ofloxacin eye drops by two different administration modes with different frequencies and intervals of application. At the beginning of cataract extraction (0.5–3 h after the last drop), 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using high-performance liquid chromatography. Results: Generally, topical ofloxacin and ciprofloxacin yielded aqueous humour levels higher than topical norfloxacin. The highest concentrations of all tested fluoroquinolones were measured after using an application mode, in which one drop was given every 15 min between 0600 hours and 0800 hours, prior to operation. When applied by this mode, ciprofloxacin achieved a mean aqueous level of 0.380 (±0.328) μg · ml⁻¹ (range 0.033–1.388 μg · ml⁻¹), norfloxacin 0.182 (0.118) μg · ml⁻¹ (range 0.038–0.480 μg · ml⁻¹) and ofloxacin 0.564 (0.372) μg · ml⁻¹ (range 0.064–1.455 μg · ml⁻¹). These mean concentrations were above the minimum inhibitory concentration (MIC₉₀), concentrations required for inhibition of 90% of pathogen strains in vitro of gram-negative bacteria, such as Proteus mirabilis and Escherichia coli. Therapeutic values above the MIC₉₀ of Staphylococcus epidermidis, the pathogen causing eye infections most frequently, were reached by 67.5% of patients after ofloxacin and by 41% after ciprofloxacin, but never after norfloxacin treatment. Conclusion: Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humour concentration. This fluoroquinolone may be an useful ophthalmic agent for topical antibacterial management, but it does not seem to be prophylactically effective against Streptococcus pneumoniae or Pseudomonas aeruginosa. Received: 22 April 1997 / Accepted: 8 June 1997     

Comparative lung delivery of salbutamol given via Turbuhaler and Diskus dry powder inhaler devices

Objective: The environmental concerns surrounding the use of chlorofluorocarbons (CFC) have led to a resurgence of interest in dry powder inhaler devices. The aim of our study was to compare two commonly used dry powder inhaler devices, namely the Turbuhaler and Diskus. Methods: Eight healthy volunteers with a mean (SEM) age of 21 years (0.8) were studied using a randomised single-investigator blind crossover design. Single doses of 1.2 mg salbutamol as Turbuhaler (12 × 100 μg) and Diskus (6 × 200 μg) were administered over 6 min. Mouth rinsing was performed after every inhalation. Lung delivery from each device was assessed by measuring the early plasma salbutamol profile at 5, 10, 15 and 20 min after inhalation. Results: Significant differences in lung delivery were found between the Diskus and the Turbuhaler for salbutamol C_max 3.21 vs 4.04 ng · ml⁻¹, respectively and C_av 2.65 vs 3.73 ng · ml⁻¹, respectively. This amounted to a 1.28-fold difference (95% CI 1.09 to 1.45) between these devices for C_max and a 1.42-fold difference (95% CI 1.57 to 1.66) for C_av. Conclusion: We have demonstrated that, in vivo, the Turbuhaler dry powder inhaler produces significantly greater lung delivery of salbutamol than the Diskus. This illustrates that dry powder inhaler devices may have different in vivo deposition characteristics. Received: 27 January 1997 / Accepted in revised form: 21 May 1997     

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     

Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses

Objectives: In order to improve the penetration of topically applied drugs in ophthalmology, the suitability of hydrophilic contact lenses (Acuvue, Vistacon, power −1.0 D) as a drug delivery system for antibiotics was tested. A prospective study was undertaken to determine the transcorneal penetration of five topically applied aminoglycosides and fluoroquinolones into the aqueous humour of patients. Methods: Two hundred and sixty-five patients undergoing cataract extraction received 0.3% gentamicin, kanamycin, tobramycin, ciprofloxacin or ofloxacin solution by two different modes of administration: either as eye drops (nine drops every 15 min, starting 2 h prior to surgery) or by means of a drug delivery system (Acuvue contact lenses soaked for 1 h in eye drop solution without preservatives, 1–5 h prior to surgery). At the beginning of cataract extraction, 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using fluorescence polarisation immuno-assays (aminoglycosides) or high-performance liquid chromatography (fluoroquinolones). Results: After soaking for 1 h in 0.3% eye drop solutions, Acuvue contact lenses released about 190–250 μg aminoglycoside and ofloxacin and 1000 μg ciprofloxacin. These amounts are considerably lower or in the same order of magnitude than obtained with application of eye drops (1350 μg). From the aminoglycosides tested, only gentamicin and tobramycin, but not kanamycin, were able to penetrate into the aqueous humour of patients. After the wearing of antibiotic-soaked lenses, mean aqueous humour concentrations were higher than after the use of eye drops. This difference reached significance in tobramycin (1.09 (1.30) μg · ml⁻¹ vs 0.49 (0.79) μg · ml⁻¹), ciprofloxacin (1.23 (0.60) μg · ml⁻¹ vs 0.38 (0.33) μg · ml⁻¹) and ofloxacin (5.55 (2.53) μg · ml⁻¹ vs 0.56 (0.37) μg · ml⁻¹). The percentage of patients with aqueous humour concentration above the MIC₉₀ of Staphylococcus epidermidis, the most common cause of postoperative endophthalmitis, was 92% and 100% after wearing ciprofloxacin- or ofloxacin-soaked lenses, respectively. Conclusion: Gentamicin and tobramycin penetrated into the aqueous humour of patients, whereas kanamycin was not able to overcome the corneal barrier. Acuvue contact lenses soaked in 0.3% eye drop solutions can release sufficient amounts of gentamicin, ciprofloxacin and ofloxacin to produce bacteriostatic concentrations in the humor aquosus. Acuvue contact lenses can be recommended as a drug delivery system for fluoroquinolones. Received: 15 October 1998 / Accepted in revised form: 16 December 1998     

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     

The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice

Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice. Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (C_max) and the time to maximum concentration (t_max) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram. Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng · ml⁻¹ · h), as was the C_max (median values 7.2 vs 2.1 ng · ml⁻¹). The t_max was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc interval at C_max was −13 to +38 ms. Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time. Received: 14 October 1996 / Accepted in revised form: 10 December 1996     

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.     

Plasma and skin suction-blister-fluid pharmacokinetics and time course of the effects of oral mizolastine

Objective:To investigate plasma and skin suction-blister-fluid pharmacokinetics of oral mizolastine in order to determine whether the drug concentration in the fluid of suction-induced skin blisters could better predict the antihistamine activity than the plasma concentration. Setting: Department of Internal Medicine, Université Paris 6. Subjects: Ten healthy male volunteers. Methods: The volunteers (mean age 26.8 years, mean weight 75.8 kg) received a single 10-mg oral dose of mizolastine at 1000 hours. The pharmacokinetic study included 11 plasma and 9 blister fluid samples and blister epidermal-roof specimens. Mizolastine was assayed by high-performance liquid chromatography (HPLC). Each volunteer also received nine intradermal injections of 5 μg histamine. Antihistamine activity was assessed as the post-treatment percentages of changes in the histamine-induced relative wheal and flare areas versus baseline. Results: Mizolastine mean C_max (SD) and median t_max were, respectively, 380 ng ⋅ ml⁻¹and 0.8 h in plasma, and 21.8 ng ⋅ ml⁻¹ and 10 h in blister fluid. Mizolastine could not be quantified in the epidermis. The maximal histamine-induced relative flare inhibition was 72.5% and was attained at the median time of 3 h post-dosing and therefore was delayed by 2.2 h with respect to the plasma t_max. Mean relative wheal inhibition, although lower, showed the same time profile. A direct relationship could not be found between drug concentrations in blister fluid and antihistamine activity. Simulated concentrations in the peripheral compartment better explain the maximum inhibition effect on flare, observed 3 h post-dosing, with a flatter hysteresis loop obtained when plotting relative flare inhibition versus plasma or blister-fluid drug concentrations. Conclusion: The mizolastine concentrations in the skin suction-blister fluid were not predictive of the antihistamine activity. Received: 23 November 1994/Accepted in revised form: 4 May 1995