The area under the plasma concentration–time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin

Objective: To determine the effects of treatment with itraconazole and rifampicin (rifampin) on the pharmacokinetics and pharmacodynamics of oral midazolam during and 4 days after the end of the treatment. Methods: Nine healthy volunteers received itraconazole (200 mg daily) for 4 days and, 2 weeks later, rifampicin (600 mg daily) for 5 days. In addition, they ingested 15 mg midazolam before the first treatment, 7.5 mg on␣the␣last day of itraconazole administration, and 4 days␣later,␣and 15 mg 1 day and 4 days after the last dose␣of␣rifampicin.␣The disposition of midazolam and its α-hydroxy metabolite was determined and its pharmacodynamic effects were measured. Results: During itraconazole treatment, or 4 days after, α-hydroxymetabolite the dose-corrected area under the plasma midazolam concentration–time curve (AUC_0–∞) was 8- or 2.6-fold larger than that before itraconazole (i.e. 1707 or 695 versus 277 ng · h · ml⁻¹), respectively. One day after rifampicin treatment, the AUC_0–∞ of midazolam was 2.3% (i.e. 4.4 ng · h · ml⁻¹) of the before-treatment value and only 0.26% of its value during itraconazole treatment; 4 days after rifampicin, the AUC_0–∞ was still only 13% (i.e. 27.1 ng · h · ml⁻¹) of the before-treatment value. The peak concentration and elimination half-life of midazolam were also increased by itraconazole and decreased by rifampicin. The ratio of plasma α-hydroxymidazolam to midazolam was greatly decreased by itraconazole and increased by rifampicin. In addition, the effects of midazolam were greater during itraconazole and smaller 1 day after rifampicin than without treatment. Conclusion: Switching from inhibition to induction of cytochrome P450 3A (CYP3A) enzymes causes a very great (400-fold) change in the AUC of oral midazolam. During oral administration of CYP3A substrates that undergo extensive first-pass metabolism, similar changes in pharmacokinetics are expected to occur when potent inhibitors or inducers of CYP3A are added to the treatment. After cessation of treatment with itraconazole or rifampicin, the risk of significant interaction continues up to at least 4 days, probably even longer. Received: 17 June 1997 / Accepted in revised form: 16 October 1997     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem

Objective: Zolpidem is a short-acting␣imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. Methods: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. Results: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration–time curve (AUC_0–∞) was 34% larger during the itraconazole phase (759 ng · h · ml⁻¹) than during the placebo phase (567 ng · h · ml⁻¹). Exophoria of the eyes by the Maddox wing test was significantly increased by itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. Conclusion: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with itraconazole and probably also with other CYP3A4 inhibitors. Received: 30 September 1997 / Accepted in revised form: 12 January 1998     

Lack of a pharmacokinetic interaction between atovaquone and proguanil

Objective: To assess the magnitude of the putative effect of atovaquone on the pharmacokinetics of proguanil and to determine whether the pharmacokinetics of atovaquone are affected by concomitant administration of proguanil, with both drugs administered for 3 days to healthy adult volunteers. Methods: This was an open-label, randomized, three-way cross-over study, in which 18 healthy volunteers received 400 mg proguanil, 1000 mg atovaquone and 1000 mg atovaquone + 400 mg proguanil. Each treatment was given once daily for 3 days with a 3-week wash-out period between each occasion. For the assay of proguanil, cycloguanil and atovaquone, blood was sampled before dosing and at regular intervals over 8 days when proguanil was given, and over 17 days when atovaquone was given. Results: The geometric mean of the area under the atovaquone plasma concentration-time curve calculated from 0 to 24 h after the last dose (AUC_0→24h) was 180 μg · ml⁻¹ · h following administration of atovaquone alone and 193 μg · ml⁻¹ · h following atovaquone with proguanil. The geometric mean AUC_0→24h for proguanil was 6296 ng · ml⁻¹ · h after proguanil alone and 5819 ng · ml⁻¹ · h following proguanil with atovaquone. The corresponding values for the metabolite cycloguanil were 1297 ng · ml⁻¹ · h and 1187 ng · ml⁻¹ · h, respectively. The geometric mean elimination half-life (t_1/2) of atovaquone was 57.1 h when given alone and 59.0 h when administered together with proguanil. The corresponding geometric mean values of t_1/2 for proguanil were 13.7 h and 14.5 h. Exploratory statistical analysis showed no important gender effects on the pharmacokinetics of atovaquone, proguanil, or cycloguanil. Conclusion: The pharmacokinetics of atovaquone and proguanil and its metabolite, cycloguanil, were not different when atovaquone and proguanil were given alone or in combination. Received: 14 October 1998 / Accepted in revised form: 8 February 1999     

Determination of the relative bioavailability of nedocromil sodium to the lung following inhalation using urinary excretion

Objective: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Methods: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. Results: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for C_max (the maximum concentration) were 5.11 ng · eq · ml⁻¹ and 4.54 ng eq · ml⁻¹, for t_max (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC_0–24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq · h · ml⁻¹ and 58.5 ng eq · h · ml⁻¹, and for t_1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were −29.5% and −29.9%, for low-density lipoprotein (LDL) cholesterol −41.0% and −42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides −33.8% and −25.8%, respectively. Conclusions: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine. Received: 17 February 1997 / Accepted in revised form: 3 November 1997     

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     

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     

The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency

Introduction: Carvedilol, a chiral compound possessing nonselective β- and α₁-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar α₁-blocking activity; only S-carvedilol possesses β-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug. Methods: The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR ≤ 30 ml · min⁻¹ (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2–9) dosing. Results: Mean with (SD) AUC_(0–24h) (ng · h · ml⁻¹) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) C_max (ng · ml⁻¹) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC_(0–24h) and C_max values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree. Conclusion: Compared with controls, average AUC_(0–24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing β-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency. Received: 26 March 1998 / Accepted in revised form: 30 January 1999     

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     

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     

Population analysis of the non-linear red blood cell partitioning of draflazine following various infusion durations

Objective: The pharmacokinetics and non-linear red blood cell partitioning of the nucleoside transport inhibitor draflazine were investigated in 19 healthy male and female subjects (age range 22–55 years) after a 15-min i.v. infusion of 1 mg, immediately followed by infusions of variable rates (0.25, 0.5 and 1 mg · h⁻¹) and variable duration (2–24 h). Methods: The parameters describing the capacity-limited specific binding of draflazine to the nucleoside transporters located on erythrocytes were determined by NONMEM analysis. The red blood cell nucleoside transporter occupancy of draflazine (RBC occupancy) was evaluated as a pharmacodynamic endpoint. Results: The population typical value for the dissociation constant K _d (%CV) was 0.648 (12) ng · ml⁻¹ plasma, expressing the very high affinity of draflazine for the erythrocytes. The typical value of the specific maximal binding capacity B_max (%CV) was 155 (2) ng · ml⁻¹ RBC. The interindividual variability (%CV) was moderate for K _d (38.9%) and low for B_max (7.8%). As a consequence, the variability in RBC occupancy of draflazine was relatively low, allowing the justification of only one infusion scheme for all subjects. The specific binding of draflazine to the red blood cells was a source of non-linearity in draflazine pharmacokinetics. Steady-state plasma concentrations of draflazine virtually increased dose-proportionally and steady state was reached at about 18 h after the start of the continuous infusion. The t_1/2βaveraged 11.0–30.5 h and the mean CL from the plasma was 327 to 465 ml · min⁻¹. The disposition of draflazine in whole blood was different from that in plasma. The mean t_1/2β was 30.2 to 42.2 h and the blood CL averaged 17.4–35.6 ml · min⁻¹. Conclusion: Although the pharmacokinetics of draflazine were non-linear, the data of the present study demonstrate that draflazine might be administered as a continuous infusion over a longer time period (e.g., 24 h). During a 15-min i.v. infusion of 1 mg, followed by an infusion of 1 mg · h⁻¹, the RBC occupancy of draflazine was 96% or more. As the favored RBC occupancy should be almost complete, this dose regimen could be justified in patients. Received: 6 February 1997 / Accepted in revised form: 12 May 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     

Pharmacokinetics of oxypolygelatine in healthy volunteers

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

Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min⁻¹ · 1.73 m⁻², group B 30–60 ml · min⁻¹ · 1.73 m⁻² and group C 15–30 ml · min⁻¹ · 1.73 m⁻²). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUC_inf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment. Received: 3 August 1998 / Accepted in revised form: 19 October 1998     

Variability of morphine disposition during long-term subcutaneous infusion in terminally ill cancer patients

Objective: To study the plasma concentrations of morphine and its glucuronides to assess the intra- and interindividual variability of the disposition of morphine administered by subcutaneous infusion in cancer patients. Methods: Blood samples were taken repeatedly in eight patients with severe cancer pain who were being treated with morphine (60–3000 mg per day) via chronic (8–160 days) subcutaneous infusion. Venous blood samples were collected at least weekly and, when possible, on 3 consecutive days after dose adaptation or any other major change in the patients' treatment. Concentrations of morphine and its glucuronides in plasma were measured after solid-phase extraction using a validated high-performance liquid chromatography assay. The stability of the morphine solutions was determined by repeated measurement of the concentrations of morphine and its degradation products in the solutions. Results: The morphine concentration in the infusion solutions remained unchanged during storage and infusion. The plasma concentrations of morphine and its glucuronides were within the ranges reported in the literature. There was, as expected, a large interindividual variability: from patient to patient, the mean of the normalised plasma concentrations ranged from 0.3 ng · ml⁻¹ · mg⁻¹ to 0.8 ng · ml⁻¹ · mg⁻¹ for morphine, from 1.0 ng · ml⁻¹ · mg⁻¹ to 3.1 ng · ml⁻¹ · mg⁻¹ for morphine-6-glucuronide and from 6.8 ng · ml⁻¹ · mg⁻¹ to 24.3 ng · ml⁻¹ · mg⁻¹ for morphine-3-glucuronide. Intraindividual variability was also important. The residual standard deviation of the mean normalised plasma concentrations calculated for each patient ranged from 26% to 56% for morphine, from 20% to 51% for morphine-6-glucuronide and from 20% to 49% for morphine-3-glucuronide. The normalised plasma concentrations of morphine and its glucuronides did not increase with dose or time, and no explanation for the pronounced pharmacokinetic intraindividual variability was found. Conclusion: During subcutaneous infusion of morphine, there is a large intra- and interindividual variability of the morphine disposition which could be of clinical relevance. Received: 5 August 1997 / Accepted in revised form: 8 October 1997     

Effect of omeprazole on the pharmacokinetics of itraconazole

Objective: To investigate the effect of omeprazole on the pharmacokinetics of itraconazole. Methods: Eleven healthy volunteers received a single dose of oral itraconazole (200 mg) on days 1 and 15 and oral omeprazole (40 mg) once daily from day 2 to day 15. Itraconazole pharmacokinetics were studied on days 1 and 15. Results: Concentrations of itraconazole were higher when it was taken alone than when it was taken with omeprazole. With concomitant omeprazole treatment, the mean AUC_0–24 and C_max of itraconazole were significantly reduced by 64% and 66%, respectively. Conclusion: Omeprazole affects itraconazole kinetics, leading to a reduction in bioavailability and C_max. These two drugs should not be used together. Received: 12 November 1997 / Accepted in revised form: 13 January 1998     

Effect of erythromycin and itraconazole on the pharmacokinetics of intravenous lignocaine

Objective: We have studied the possible interaction of erythromycin and itraconazole, both inhibitors of cytochrome P450 3A4 isoenzyme (CYP3A4), with intravenous lignocaine in nine healthy volunteers using a randomized cross-over study design. Methods: The subjects were given oral placebo, erythromycin (500 mg three times a day) or itraconazole (200 mg once a day) for 4 days. Intravenous lignocaine 1.5 mg · kg⁻¹ was given with an infusion for 60 min on the fourth day of pretreatment with placebo, erythromycin or itraconazole. Timed plasma samples were collected until 11 h. The concentrations of lignocaine and its metabolite monoethylglycinexylidide (MEGX) were measured by gas chromatography. Results: The area under the lignocaine concentration-time curve was similar during all three phases but erythromycin significantly increased the elimination half-life of lignocaine from 2.5 to 2.9 (0.7) h compared with placebo. Following itraconazole administration, t_1/2 was 2.6 h. The values for plasma clearance and volume of distribution at steady state were similar during all the phases. Compared with placebo and itraconazole, erythromycin significantly increased MEGX peak concentrations by approximately 40% and AUC_(0–11 h) by 45–60%. Conclusion: The plasma decay of lignocaine administered intravenously is virtually unaffected by the concomitant administration of erythromycin and itraconazole. However, erythromycin increases the concentrations of MEGX, which indicates that erythromycin either increases the relative amount of lignocaine metabolized via N-de-ethylation or decreases the further metabolism of MEGX. Further studies are necessary to elucidate the clinical significance of the erythromycin-induced elevated concentrations of MEGX during prolonged intravenous infusions of lignocaine. Received: 8 January 1998 / Accepted in revised form: 8 June 1998     

Helicobacter pylori clearance and serum gastrin and pepsinogen I concentrations in omeprazole treatment of duodenal ulcer patients

Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients undergoing omeprazole treatment. Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females, aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels. Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml⁻¹, SD 32.0 pg · ml⁻¹ vs 133.9 pg · ml⁻¹, SD 71.6 pg · ml⁻¹, P < 0.01), and pepsinogen I (111.0 ng · ml⁻¹, SD 36.7 ng · ml⁻¹ vs 253.6 ng · ml⁻¹, SD 64.8 ng · ml⁻¹, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD 67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity to predict antral H. pylori clearance. Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia I probably provides a non-invasive alternative for predicting H. pylori clearance. Received: 22 August 1996 / Accepted in revised form: 1 October 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     

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration

Objective: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). Methods: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS–MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. Results: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg · ml⁻¹ for the 0.25 mg dose to 400 pg · ml⁻¹ for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% · h for lymphocyte suppression, 107, 186, 202 and 348% · h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC₅₀ values, 30 pg · ml⁻¹ and 7.3 pg · ml⁻¹ for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. Conclusion: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling. Received: 27 January 1997 / Accepted in revised form: 5 August 1997     

Plasma esterases in cystic fibrosis: the impact of a respiratory exacerbation and its treatment

Objectives: To determine the effect of an exacerbation of respiratory symptoms in cystic fibrosis (CF) on the activities of plasma benzoylcholinesterase and butyrylcholinesterase. Methods: Twenty-nine patients with CF in a respiratory exacerbation and 27 healthy volunteers matched for age and sex were recruited. Blood was obtained from the patients when commencing antibiotic treatment and 14 days later on completion of treatment. One blood sample was taken from the healthy volunteers. The activities of benzoylcholinesterase and butyrylcholinesterase were determined by spectrophotometric assay. The circulating inflammatory markers, C-reactive protein and neutrophil elastase-α₁antiproteinase complex were also measured. Results: Benzoylcholinesterase activity was significantly (P = 0.001) lower in patients at the start of a respiratory exacerbation, compared with healthy controls [mean (SD): 917 (274) versus 1191(298) nmol · ml⁻¹ · min⁻¹]. Benzoylcholinesterase activity increased significantly in patients to 1013 (237) nmol · ml⁻¹ · min⁻¹, following a course of antibiotic treatment (P = 0.006). Butyrylcholinesterase activity was also lower (P = 0.001) in patients at the start of a respiratory exacerbation, compared with healthy controls [5.54 (1.64) versus 7.01 (1.79) μmol · ml⁻¹ · min⁻¹], and increased significantly in the patients to 6.31 (1.58) μmol · ml⁻¹ · min⁻¹ following treatment (P = 0.006). Conclusion: We demonstrated significant suppression of plasma esterase activities during an exacerbation of respiratory symptoms in CF, which was only partially reversed after antibiotic treatment. Further studies are needed to examine other pathways of drug metabolism in this group of chronically infected patients. Received: 8 June 1998 / Accepted in revised form: 18 September 1998