Concerns about infertility risks among pediatric oncology patients and their parents.

BACKGROUND: Given pediatric cancer patients are living into adulthood, parents and patients need to be informed about fertility-related side effects of their particular treatment. PROCEDURE: We surveyed 97 parents of pediatric patients of all ages as well as 37 adolescent patients of 14 years or older who were presented for care at the Lucile Packard Children's Hospital (LPCH) at the Stanford University Medical Center. We estimated the potential infertility risk (low, intermediate, and high) based on the child's treatment regimen. RESULTS: In contrast to our hypothesis, the majority of parents in all three risk categories were concerned about fertility-related side effects of cancer treatment. Many parents with children at low risk were concerned (58.3%) whereas not all parents with children at intermediate or high risk were concerned, 61.5% and 73.3% respectively, P = 0.43. Indeed, over 50% of all parents were erroneously concerned that cancer therapies cause DNA damage to their child's eggs (or sperm). Only 29.9% of parents were satisfied with the amount of information received. Similar patterns were seen among the adolescent patient sample. CONCLUSIONS: Parents of pediatric cancer patients and teenage patients have concerns about fertility-related side effects regardless of treatment received. Targeted education about infertility risk before and after treatment can address these gaps.

Determination of the bioavailability of [14C]-hexaminolevulinate using accelerator mass spectrometry after intravesical administration to human volunteers.

Hexaminolevulinate (HAL) is a diagnostic agent that allows the visualization of tumor tissue in the bladder by fluorescence cystoscopy. It is administered intravesically via a catheter for 1 hour, followed by blue light bladder inspection to induce selective red tumor fluorescence. Hexaminolevulinate should ideally be confined to the bladder only, but it is likely that some absorption occurs during administration, and therefore the systemic bioavailability is of interest. The bioavailability of HAL was determined by intravesical and intravenous administration of [14C]-HAL hydrochloride to 8 human volunteers. To reduce the radiation dose as low as possible, the ultrasensitive analytical technique of accelerator mass spectrometry was used to measure [14C]-HAL. The bioavailability of [14C]-HAL after intravesical and intravenous administration was determined from the respective area under the curve based on total radioactivity and was determined to be 7% (range, 5%-10%; 90% confidence interval). The systemic absorption of [14C]-HAL after intravesical administration is low and supports previous clinical experience with HAL showing no systemic side effects.

A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone.

A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Beta-2-adrenoceptor-mediated hypokalemia and its abolishment by oxprenolol.

The time course and concentration-effect relationship of terbutaline-induced hypokalemia was studied, using computer-aided pharmacokinetic-dynamic modeling. Subsequently we investigated the efficacy of oxprenolol in antagonizing such hypokalemia, together with the pharmacokinetic interaction between both drugs. Six healthy subjects were given a 0.5 mg subcutaneous dose of terbutaline on two occasions: 1 hour after oral administration of a placebo and 1 hour after 80 mg oxprenolol orally. In the 7-hour period after terbutaline administration, plasma samples were taken for determination of plasma potassium levels and drug concentrations. The sigmoid Emax model offered a good description of the relation between terbutaline concentrations and potassium effects. Oxprenolol caused decreases of 65% and 56% of terbutaline volume of distribution and clearance, respectively, and an increase of 130% of its AUC. In spite of higher terbutaline concentrations after oxprenolol pretreatment, the hypokalemia was almost completely antagonized by the beta 2-blocking action.

Pharmacokinetic-pharmacodynamic modeling of terbutaline bronchodilation in asthma.

The study of terbutaline pharmacodynamics in patients with asthma is hampered by interfering stimuli when steady-state methods are employed. With pharmacokinetic-dynamic modeling, many of these interferences can be avoided. Using this technique, we studied the effect of terbutaline on lung function in 10 asthmatic patients with greater than 15% lung function reversibility. Terbutaline plasma concentrations, forced expiratory volume in 1 second (FEV1) airway resistance (Raw), and specific airway conductance (sGaw) were measured before and during 7 hours after subcutaneous dosing with 0.75 mg terbutaline. A hyperbolic concentration-effect relation was found. Fitting the time course of the effects required an effect compartment in the integrated model. Thus the delay between plasma concentration and effect time course was characterized by the rate constant ke0. Essentially the same ke0 was found for FEv1, Raw, and sGaw, indicating that the concerning receptors are "localized" in the same pharmacokinetic compartment. Of the lung function measures, sGaw was less sensitive to terbutaline than Raw and FEV1, whereas the latter tended to be the most sensitive one.

The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine.

The disposition of oxcarbazepine was studied in 12 young and 12 elderly healthy male and 12 young and 12 elderly healthy female volunteers, with emphasis on the influence of age. Oxcarbazepine was administered as a single dose of either 300 mg (men) or 600 mg (women), followed by multiple-dose (300 mg) administration twice a day for 7 days (men) or 6 days (women). Semilogarithmic plasma concentration-time curves showed an increasing decline at decreasing concentrations. Accumulation of the pharmacologically active metabolite monohydroxycarbamazepine was found to be more than one would anticipate on the basis of linear and unchanged pharmacokinetics. Saturation did not seem to occur at the level of renal excretion. No apparent differences between male and female volunteers were observed. A significant higher maximum concentration, higher area under the curve parameters, and a lower elimination rate constant were observed in the elderly. These observations are in line with a smaller renal clearance of monohydroxycarbamazepine in the elderly group. In a clinical situation, these age-related differences are not likely to have important implications. In general, treatment with oxcarbazepine was well tolerated.

Continuous infusion of chemotherapy on an outpatient basis via a totally implanted venous access port.

170 patients were treated with continuous infusion of epirubicin, mitoxantrone, carboplatin or 5-fluorouracil through an implanted venous access port with a portable infusion pump. A total of 440 cycles were given on an outpatient basis. The patients were instructed how to dissolve their drugs and to change the syringes. The complication rate was low. 10 patients developed a thrombosis of the subclavian vein, resulting in cessation of therapy in 5. Pulmonary embolism occurred twice, in 1 patient during a period of subclavian vein thrombosis. Needle dislocation occurred 6 times and catheter occlusion 20 times. Patency was restored with saline or urokinase. Local infection occurred 3 times and systemic infection only once. This technique is suitable for continuous infusion of different cytostatic drugs on an outpatient basis. Patients were able to prepare their drugs at home and the system can remain in situ for 3 weeks without increasing the complication rate.

A simple optical fiber device for quantitative fluorescence microscopy of single living cells.

A simple and relatively inexpensive system is described for obtaining quantitative fluorescence measurements on single living cells loaded with a fluorescent probe to study cell physiological processes. The light emitted from the fluorescent cells is captured by and transported through an optical fiber. After passage through appropriate filters the light is measured using a photomultiplier tube. The optical fiber is mounted in one of the microscope outlets. Signals derived from the photomultiplier are converted to voltage, amplified, and displayed on a recorder. In the excitation pathway a shutter control unit is mounted. With this control unit the period that the excitation pathway is 'opened' and 'closed' can be adjusted, to reduce cell damage and/or bleaching of the probe. This option allows time-lapse recording of experiments up to 1 h. We have used this set-up with a single and dual emission fluorescent probe to determine intracellular calcium concentrations and pH, respectively. In Fluo-3-loaded K562 target cells bound to natural killer cells, a temporary rise in [Ca2+]i was accompanied by bleb formation. The simple construction of this set-up is interchangeable between different types of fluorescence microscopes and can easily be combined with other microscopy techniques, e.g., patch clamp.

A randomized controlled trial of artemotil (beta-arteether) in Zambian children with cerebral malaria.

The efficacy and safety of intramuscular artemotil (ARTECEF) was compared to intravenous quinine in African children with cerebral malaria. This prospective block randomized open-label study was conducted at two centers in Zambia. Subjects were children aged 0 to 10 years of age with cerebral malaria and a Blantyre Coma Score of 2 or less. Ninety two children were studied; 48 received artemotil and 44 quinine. No significant differences in survival, coma resolution time, neurologic sequelae, parasite clearance time, and fever resolution time were seen between the two regimens. Rates for negative malaria smears one month after therapy were similar in both groups. Artemotil was a well-tolerated drug in the 48 patients in this study. It appears to be at least therapeutically equivalent to quinine for the treatment of pediatric cerebral malaria. It has the advantage of being able to be given intramuscularly once daily for only five days.

A pharmacokinetic and pharmacodynamic comparison of metoprolol CR/ZOK with a conventional slow release preparation.

The plasma concentration-time profile and hemodynamic effects of metoprolol after the administration of metoprolol CR/ZOK, a multiple-unit controlled release formulation and a conventional slow release formulation, metoprolol Durules (Astra, AB Hässle, Mölndal, Sweden) once daily, were investigated in 12 healthy men. Data were collected over one 24-hour dose interval at steady state after 5 days of treatment. The study was randomized, three-way, crossover double-blind comparison of metoprolol CR/ZOK 200 mg, metoprolol Durules 200 mg and placebo. The reduction in exercise heart rate compared with placebo treatment was used as a measure of beta 1-blockade. The metoprolol plasma concentration-time profile during treatment with metoprolol CR/ZOK was smooth and uniform, showing a more constant release profile than that obtained with metoprolol Durules. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR/ZOK compared with metoprolol Durules (P less than .01). The Fluctuation Index of plasma metoprolol concentration was significantly smaller for metoprolol CR/ZOK than for metoprolol Durules (P less than .001). The pharmacokinetic differences between the formulations also produced differences in the time profiles of exercise heart rate. The percentage fluctuation in exercise heart rate over the dose interval tended to be smaller for metoprolol CR/ZOK. At the start and the end of the dosing interval, the CR/ZOK formulation was significantly more effective (P less than .01). These results indicate that Metoprolol CR/ZOK has a more sustained time profile of beta 1-blockade at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

No influence of single intravenous doses of omeprazole on theophylline elimination kinetics.

The influence of single intravenous doses of omeprazole on the pharmacokinetics of intravenously administered theophylline was studied in eight healthy male volunteers. In a partially randomized three-period crossover design, an IV infusion of theophylline (400 mg over 30 min) was combined with IV omeprazole (either 40 mg over 2.5 min or 80 mg over 5 min) or with IV placebo (over 2.5 min). Theophylline and omeprazole plasma concentrations were measured over 24 hours after the start of the infusions and pharmacokinetic parameters were calculated. The theophylline plasma concentration-time profiles after omeprazole coadministration were virtually identical to the corresponding profile after placebo administration. For each of the pharmacokinetic parameters of theophylline, the 90% confidence intervals of the omeprazole coadministrations were within the 80 to 120% bioequivalence range with respect to the placebo coadministration. Omeprazole plasma concentrations indicated a biexponential decline in most subjects, with a more rapid elimination after the 40-mg than after the 80-mg dose (P less than .01). Doubling the dose caused an almost three-fold increase of AUC resulting in a difference in clearance (P less than .02), whereas the volume of distribution was similar. The results of this study indicate that the metabolism of theophylline is not affected by single intravenous doses of omeprazole. The nonlinear pharmacokinetics of omeprazole are ascribed to saturation of its main metabolizing enzyme, S-mephenytoin hydroxylase.

Steady-state pharmacodynamics and pharmacokinetics of warfarin in the presence and absence of telmisartan in healthy male volunteers.

The effects of multiple-dose telmisartan on the steady-state pharmacodynamics and pharmacokinetics of warfarin were assessed in 12 healthy young males in an open-label, single-period study conducted over 30 days. Subjects received loading doses of oral once-daily warfarin on days 1 to 5, which were individually adjusted at days 6 and/or 9 to attain stable predose prothrombin time values (INRpre) of between 1.2 and 1.8 by the end of medication phase 1 (day 14). From days 15 to 24 (medication phase 2), subjects received oral once-daily telmisartan 120 mg in addition to individualized oral doses of once-daily warfarin. On days 25 to 31 (medication phase 3), oral once-daily warfarin was again administered alone at individualized doses. Under steady-state conditions, INRpre remained unchanged during medication phases 1, 2, and 3. The difference between phases 1 and 3 was -0.04 (95% confidence interval [CI]: -0.7 to 0.10) and between phases 2 and 1 was 0.03 (95% CI: -0.11 to 0.10). Mean trough plasma warfarin concentrations (Cpre) were stable during medication with warfarin alone but showed a small, although statistically significant, decrease during the combined-medication phase. The point estimate of the ratio of phase 2/phase 1 was 0.89 (95% CI: 0.84 to 0.95). The decrease in Cpre did not result in decreased anticoagulation. This suggests that the extent of pharmacokinetic interaction between telmisartan and warfarin is limited, and since telmisartan had no effect on INRpre and the concomitant medication was well tolerated, there is no evidence for a clinically relevant interaction between telmisartan and warfarin.

The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers.

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Rational experimental design for bioanalytical methods validation. Illustration using an assay method for total captopril in plasma.

Generally, bioanalytical chromographic methods are validated according to a predefined programme and distinguish a pre-validation phase, a main validation phase and a follow-up validation phase. In this paper, a rational, total performance evaluation programme for chromatographic methods is presented. The design was developed in particular for the pre-validation and main validation phases. The entire experimental design can be performed within six analytical runs. The first run (pre-validation phase) is used to assess the validity of the expected concentration-response relationship (lack of fit, goodness of fit), to assess specificity of the method and to assess the stability of processed samples in the autosampler for 30 h (benchtop stability). The latter experiment is performed to justify overnight analyses. Following approval of the method after the pre-validation phase, the next five runs (main validation phase) are performed to evaluate method precision and accuracy, recovery, freezing and thawing stability and over-curve control/dilution. The design is nested, i.e., many experimental results are used for the evaluation of several performance characteristics. Analysis of variance (ANOVA) is used for the evaluation of lack of fit and goodness of fit, precision and accuracy, freezing and thawing stability and over-curve control/dilution. Regression analysis is used to evaluate benchtop stability. For over-curve control/dilution, additional to ANOVA, also a paired comparison is applied. As a consequence, the recommended design combines the performance of as few independent validation experiments as possible with modern statistical methods, resulting in optimum use of information. A demonstration of the entire validation programme is given for an HPLC method for the determination of total captopril in human plasma.

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations.

In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300 (300 mg), Adizem XL (300 mg), Cardizem (300 mg) and Dilacor (240 mg). Sixteen healthy male volunteers (aged 22.9 +/- 3.3 years, range 19-31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (cmin), the maximum plasma concentration (cmax), the time to reach that concentration (tmax), the time interval during which the plasma concentration exceeds 50% of cmax (t50), the area under the plasma concentration-time curve (AUC72-96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC72-96 (AUCNDM and AUCDAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng.mL-1 in the morning hours were observed for Dilacor (240 mg) and Adizem XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.

Unaltered ibuprofen-induced faecal blood loss upon coadministration of moclobemide.

The influence of moclobemide on ibuprofen-induced faecal blood loss was investigated in 24 volunteers. The subjects were randomly assigned to one of two groups and received from day 1 until day 14 either moclobemide 150 mg t.i.d. (group A) or placebo t.i.d. (group B). On days 8-14, when moclobemide concentrations in group A were at steady state, all volunteers additionally received ibuprofen (600 mg t.i.d). From day 15 to 21, all subjects received placebo alone. Faecal blood loss (FBL) was quantified daily by the 51Cr-labelled erythrocyte method. As expected for ibuprofen, a significant increase in FBL during the second week of the study was observed. There was no difference in FBL between the two treatment groups (moclobemide or placebo). Similar FBL values were observed in both groups (group A vs B): during the first week the FBL values were (mean +/- SD) 0.40 +/- 0.23 ml/day vs 0.55 +/- 0.53 ml/day on days 1-3 and 0.40 +/- 0.21 ml/day vs 0.37 +/- 0.13 ml/day on days 4-7. The increase in FBL during the second week was comparable in both groups, with and without moclobemide (days 8-10: 0.78 +/- 0.59 ml/day vs 0.80 +/- 0.58 ml/day; days 11-14: 1.49 +/- 0.95 ml/day vs 1.28 +/- 0.62 ml/day). A decline in FBL was observed during the third week under placebo in both groups, but baseline values were not reached during the observation period. Again there was no difference between the two groups (days 15-17: 0.91 +/- 0.52 ml/day vs 0.92 +/- 0.47 ml/day; days 18-21: 0.74 +/- 0.30 ml/day vs 0.68 +/- 0.48 ml/day). No statistically significant interaction was found between week and type of treatment, indicating that no significant influence of moclobemide on the ibuprofen-induced faecal blood loss occurred. No notable pharmacokinetic interaction between moclobemide and ibuprofen was observed. Moclobemide plasma concentration-time profiles with and without concomitantly administered ibuprofen were superimposable. The results demonstrate that the concomitant administration of ibuprofen and moclobemide to healthy volunteers does not result in a clinically significant interaction, either at the pharmacodynamic (faecal blood loss) or at the pharmacokinetic level.

Pharmacokinetic studies in healthy volunteers in the context of in vitro/in vivo correlations.

A multitude of in vivo variables can influence systemic drug absorption after intake of an oral formulation. For the measurement of consistent in vivo parameters within and between pharmacokinetic studies it is of primary importance that such variables be recognized. Consequently, as many variables as possible should be eliminated or controlled by proper study designs to prevent (or minimize) their disturbance of in vitro/in vivo correlations. The possible influences of some important variables are elaborated and discussed in this paper. The influences of food can be anticipated and controlled against the background of gastrointestinal physiology with and without food and its interplay with the dosage form. Food, and also posture and exercise, may influence splanchnic-hepatic blood flow which may substantially affect the absorption of drugs with a high first-pass metabolism. The influence of the discussed variables may be modified by the dosage form of a particular drug. Single dose studies are appropriate for studying immediate release formulations and in the development of controlled release formulations. Multiple dose studies are preferred for the formal validation of controlled release formulations.

Pharmacokinetics of [14C]-labelled Losigamone and enantiomers after oral administration to healthy subjects.

Losigamone ((+/-)-(R*,S*)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2 (5H)-furanone; AO-33) is a new potential antiepileptic drug undergoing clinical development. In a crossover study, 200 mg [14C]-labelled Losigamone, as well as 100 mg of each of the unlabelled enantiomers, was administered to 5 healthy volunteers as an oral suspension. The objectives of the study were to determine the mode of elimination, the excretion balance, metabolic profile, the in vitro and in vivo binding to plasma proteins and the pharmacokinetics of both enantiomers in plasma. From the plasma concentration-time profiles of [14C]-radioactivity and unchanged Losigamone it can be concluded that the absorption of Losigamone occurs very rapidly and the plasma concentration of the parent compound versus total radioactivity was consistently about 40%. An overall recovery of total radioactivity of about 97% with 85% in urine and 12% in faeces was found. Protein binding was 50%. Losigamone was extensively metabolized, with only traces of unchanged drug found in urine. The predominant metabolic pathways are hydroxylation and conjugation. After administration of the pure enantiomers, significant differences in pharmacokinetics were observed. The mean oral clearance of the (-)-enantiomer was 1863 ml/min and of the (+)-enantiomer was 171 ml/min. There was no chiral inversion after administration of the enantiomers.