Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy

OBJECTIVES: This study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid. METHODS: Twenty-two patients (males and females, 18-55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days -7 and -1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid. RESULTS: Seventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (+/- SD) maximum observed plasma concentration (C(max)) [70.8 +/- 20.5 vs 69.2 +/- 27.0 microg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC(12)) [689.3 +/- 250.4 vs 661.8 +/- 251.3 microg . h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day -1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the 'no effect' range of 0.80-1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy. CONCLUSION: There is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.     

Modification of phenytoin clearance by valproic acid in normal subjects.

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.     

Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study

Summary Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination ( phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.     

Single dose and steady state pharmacokinetics of valproic acid in adult epileptic patients.

The pharmacokinetics of valproic acid was studied in ten adult epileptic patients (five f + five m, 19-48 years; 28 +/- 12, mean +/- SD, and body mass 45 to 70 kg; 61 +/- 7, mean +/- SD) both after single dose and at the steady state. Sodium valproate was given in a 900 mg single oral dose on the first day of therapy, followed by 3 x 300 mg/day during the three subsequent days (at the intervals of 7, 8 and 9 h). During the first day, plasma was obtained just before the drug was given, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10 and 12 h after drug administration. On the fourth day of therapy (at steady state), plasma was obtained just before the next dose and 3 h after the drug administration. The plasma concentrations of valproic acid were measured by gas chromatography with flame ionization detection, after extraction with chloroform. The pharmacokinetic parameters, necessary to define the pharmacokinetics of valproic acid, were calculated both after single dose: Cmax, tmax, kel, t1/2, Vd, AUC and Cl, and at steady state: Cminss Cmaxss and Fl%. These parameters, as well as plasma levels of the drug, were used to describe the pharmacokinetic behaviour of valproic acid under these clinical conditions, and mainly were in agreement with the values published in the literature.     

Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders.

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.     

Valproic acid and diazepam interaction in vivo

1 The effect of oral administration of sodium valproate (1500 mg daily) on the distribution and elimination kinetics of intravenously administered diazepam in six healthy volunteers has been studied. 2 During valproate administration the unbound fraction of diazepam in serum increased approximately two fold. This was accompanied by a significant increase in apparent volume of distribution and plasma clearance of diazepam. 3 There was a positive correlation between the change in free fraction and the increase in both apparent volume of distribution and plasma clearance of the drug. 4 The concentration of unbound diazepam in serum (calculated from the percent free diazepam and total serum concentration) was significantly higher during valproate administration. Both the intrinsic clearance and volume of distribution of unbound drug were significantly reduced. 5 Mean serum N-desmethyldiazepam levels were significantly lower during valproate coadministration. 6 These results suggest that valproic acid displaces diazepam from plasma protein binding sites and inhibits its metabolism.     

糖皮质激素对重度颅脑损伤患者血浆TNF-α、 IL-6、IL-8水平的影响

目的 研究糖皮质激素对重度颅脑损伤患者血浆TNF-α、IL-6、IL-8水平的影响.方法 随机将重度颅脑损伤患者分为激素治疗组(18 例)与非激素治疗对照组(18 例),激素组给予地塞米松 10 mg/d,共 7 d.正常组选择健康体检者 18 例.采用 ELSIA法检测两组患者伤后第 1、2、3、7、14 d血浆中 TNF-α、IL-6、IL-8含量.结果 在颅脑损伤第 1、2、3天激素组血浆 TNF-α、IL-6、IL-8水平明显高于正常组(P<0.01),在第 7、14 天明显低于非激素组(P<0.01),但与正常组比较差异无统计学意义(P>0.05).非激素组血浆TNF-α、IL-6、IL-8水平在各时间点均明显高于正常组 (P<0.01).结论 糖皮质激素对损伤早期血浆TNF-α、IL-6、IL-8显著升高无明显影响,但至恢复期使血浆TNF-α、IL-6、IL-8明显降低.     

不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响

目的：研究不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度的影响。方法：回顾性分析某院270例丙戊酸血药浓度监测报告,记录患者姓名、年龄、体质量、丙戊酸的用法与用量、联合用药情况（合用药品及其用法与用量）和血药浓度监测结果。分析不同丙戊酸盐和丙戊酸剂型对丙戊酸标准血药浓度的影响。结果：二元Logistic回归分析结果表明丙戊酸盐类型和剂型对标准血药浓度有显著影响（P<0.05）;丙戊酸镁的标准血药浓度[（9.18±3.54）μg·kg·mL^-1·mg^-1]大于丙戊酸钠盐的标准血药浓度[（6.76±2.54）μg·kg·mL^-1·mg^-1];丙戊酸缓释片的标准血药浓度[（8.38±3.49）μg·kg·mL^-1·mg^-1]大于丙戊酸普通片的标准血药浓度[（6.88±2.54）μg·kg·mL^-1·mg^-1],差异均具有显著性（P<0.05）。结论：不同丙戊酸盐和丙戊酸剂型对丙戊酸血药浓度存在明显影响,如何选择丙戊酸盐和丙戊酸剂型对丙戊酸的合理运用具有重要意义。     

Generic Substitution and Bioequivalence of Sodium Valproate at Steady-State in Healthy Volunteers

The objective of this study was to investigate the bioequivalence of three marketed formulations of sodium valproate 500mg enteric-coated tablets at steady-state in healthy, adult male human subjects in a multiple-dose cross-over study. Sodium valproate tablets were administered twice daily for four days and only the morning dose was administered on the fifth day during each period. Blood samples were collected pre-dose on days 1–5, and post-dose on day 5 over 12 hours in each period. Plasma concentrations were determined using a validated high performance liquid chromatography method. Both Encorate and Epilex (generic products) were bioequivalent to Vaparin (reference product) and all three products were well tolerated by all subjects.     

Effect of clarithromycin on the pharmacokinetics of cabergoline in healthy controls and in patients with Parkinson's disease

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean Cmax and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.     

The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans

Summary The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37°C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34–182% (p<0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50–87%,p<0.01) than in fasting samples (10–50%,p<0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (p<0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.     

Effect of rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics of risperidone

The authors studied the effect of rifampin, a dual inducer of CYP3A and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of risperidone in humans. Ten healthy male subjects were treated daily for 7 days with 600 mg rifampin or with placebo. On day 6, a single dose of 1 mg risperidone was administered. Plasma risperidone and 9-hydroxyrisperidone concentrations were measured. Rifampin significantly decreased the mean area under the plasma concentration-time curve by 51% for risperidone, by 43% for 9-hydroxyrisperidone, and by 45% for the active moieties (risperidone + 9-hydroxyrisperidone). Rifampin also decreased the peak plasma concentration of risperidone by 38%, 9-hydroxyrisperidone by 46%, and the active moieties by 41%. The apparent oral clearance of risperidone approximately doubled after rifampin treatment. Thus, rifampin reduced the exposure to risperidone, probably because of a decrease in its bioavailability through the induction of CYP3A and probably P-glycoprotein.     

Absorption rate and bioavailability of valproic acid and its sodium salt from rectal dosage forms

Summary Rectal and oral absorption of valproic acid and its sodium salt by man were compared to explore the possibility of rectal administration of the drug. The plasma concentration of valproic acid was measured by gas chromatography after a single oral dose of sodium valproate 600 mg, and after single rectal doses of sodium valproate 600 mg and valproic acid 520 mg, in a cross-over study in 7 volunteers. The rectal dosage forms included fatty suppositories and aqueous solutions. Compared with oral administration, rectal absorption of sodium valproate from an aqueous micro-enema was fast and complete. The free acid was absorbed more rapidly from fatty suppositories than was the sodium salt. The absorption rate from the rectum increased with the dose of valproic acid. Both findings are consistent with a diffusion — absorption mechanism based on the pH-partition hypothesis. Differences in the chemical composition of the fatty suppository base were not reflected in differences in absorption rate and relative bioavailability. No essential difference in absorption rate was observed if volunteers remained lying or sitting during the experiment. Rectal dosing with valproic acid 520 mg dissolved in 4 ml suppositories, twice a day resulted in steady-state plasma concentrations of 50 to 100 µg · ml^–1, within the therapeutic range.Data have been presented in: F. Moolenaar, Ph. D. Thesis, Groningen, The Netherlands     

Risperidone does not affect steady-state pharmacokinetics of divalproex sodium in patients with bipolar disorder

OBJECTIVE: Divalproex sodium can interact with many drugs in which combination treatments are used; it can increase plasma concentrations of some drugs by inhibiting metabolism and can increase the free fractions of other medications by displacing them from plasma proteins. The combination of risperidone and divalproex sodium is used to treat the manic phase of bipolar disorder. However, the effect of risperidone on the pharmacokinetics of valproate has not previously been systematically studied. The aims of this study were to determine the effect of repeated doses of oral risperidone on the pharmacokinetics of valproate in subjects stabilised on divalproex sodium and to document the safety of this combination. STUDY DESIGN: A multicentre, observational, randomised, parallel group, single-blind, placebo-controlled drug interaction study. PATIENTS: Twenty-two patients with bipolar disorder, in remission, were studied. METHODS: All subjects were treated with divalproex sodium 1000 mg/day monotherapy on days 1-14. Thereafter, subjects continued to take divalproex sodium for days 15-28; they also received adjunctive treatment with either placebo (n = 11) or risperidone (n = 11) 2mg once daily on days 15 and 16, and 4 mg once daily on days 17-28. Serial blood sampling was performed throughout to determine the plasma concentrations of valproate, risperidone and 9-hydroxy-risperidone. RESULTS: On analysis, steady-state pharmacokinetic parameters (peak plasma concentrations [C(max)], time to C(max,) area under the concentration-time curve) of valproate were of the same order of magnitude on day 14 (monotherapy) and day 28 (valproate plus risperidone or placebo), with no period effect. The parameters on day 28 were similar in the risperidone and placebo treatment groups, showing that risperidone, as adjunctive treatment, had no influence on the steady-state pharmacokinetics of valproate. Although there were more adverse events reported in the risperidone group compared with the placebo group (ten vs seven, respectively), none of them were serious or necessitated withdrawal. No clinically relevant changes in laboratory parameters, vital signs or ECG-tracings were observed in either group. CONCLUSION: These results indicate that adjunctive risperidone treatment had no influence on the steady-state pharmacokinetics of valproate and this combination was safe and well tolerated.     

Potential interaction between valproic acid and doripenem

A potential interaction between valproate (VPA) and doripenem leading to decreased valproic acid concentrations in two patients is described. In the first patient case, a 54-year-old female presented to the emergency department following a seizure episode after stopping her medications a few days prior. She was given a 1500 mg (23 mg/kg) intravenous (IV) bolus dose of valproate and restarted on her home regimen of divalproex sodium 750 mg daily which quickly resulted in valproic acid blood concentrations within the reference range. The patient was later started on doripenem 500 mg IV every 8 hours and subsequent valproic acid concentrations decreased by 62%. The second patient was a 54-year-old female transferred from an outlying facility following a motor vehicle accident. The patient was receiving valproate 1250 mg IV every 8 hours for seizure prophylaxis following a traumatic brain injury. She developed pneumonia and was started on doripenem 500mg IV every 8 hours. Valproic acid concentrations decreased by 69% within two days. This case report describes two patients receiving concomitant valproate and doripenem resulting in a 62% and 69% reduction in valproic acid concentration.     

Concomitant use of mirtazapine and phenytoin: a drug-drug interaction study in healthy male subjects

OBJECTIVE: The objectives of this study were to assess the effect of mirtazapine on steady-state pharmacokinetics of phenytoin and vice versa and to assess tolerability and safety of the combined use of mirtazapine and phenytoin. METHODS: This was an open-label, randomised, parallel-groups, single-centre, multiple-dose pharmacokinetic study. Seventeen healthy, male subjects completed either treatment A [nine subjects: daily 200 mg phenytoin for 17 days plus mirtazapine (15 mg for 2 days continuing with 30 mg for 5 days) from day 11 to day 17] or treatment B [eight subjects: mirtazapine, daily 15 mg for 2 days continuing with 30 mg for 15 days plus phenytoin 200 mg from day 8 to day 17]. Serial blood samples were taken for kinetic profiling on the 10th and 17th days of treatment A and on the 7th and 17th days of treatment B. Induction of CYP 3A by phenytoin was evaluated by measuring the ratio of 6 beta-hydroxycortisol over cortisol on the 1st, 7th and 17th days of treatment B. RESULTS: Co-administration of mirtazapine had no effect on the steady-state pharmacokinetics of phenytoin, i.e. the area under the plasma concentration-time curve (AUC)(0-24) and peak plasma concentration (C(max)) remained unchanged. The addition of phenytoin to an existing daily administration of mirtazapine resulted in a mean (+/-SD) decrease of the AUC(0-24) from 576+/-104 ng h/ml to 305+/-81.6 ng h/ml and a mean decrease of C(max) from 69.7+/-17.5 ng/ml to 46.9+/-10.9 ng/ml. Induction of CYP 3A by phenytoin is confirmed by the significantly ( P=0.001) increased 6beta-hydroxycortisol/cortisol ratio from 1.74+/-1.00 to 2.74+/-1.64. CONCLUSION: Co-administration of mirtazapine did not alter the steady-state pharmacokinetics of phenytoin. The addition of phenytoin to an existing daily administration of mirtazapine results in a decrease of the plasma concentrations of mirtazapine by 46% on average, most likely due to induction of CYP 3A3/4.     

Pharmacokinetics of valpromide after oral administration of a solution and a tablet to healthy volunteers

Summary The pharmacokinetics of valpromide, a primary amide of valproic acid, was investigated in 6 healthy, adult male volunteers, each of whom was given 900 mg as a marketed, enteric-coated tablet and a solution. Valpromide was biotransformed to valproic acid after the administration of the tablet and the solution with a bioavailability of 0.79±0.24 and 0.77±0.12, respectively, relative to a marketed tablet of valproic acid. The absorption of valpromide was not rate-limited by dissolution. As a solid, non-hygroscopic, neutral prodrug of valproic acid, valpromide may be a good alternative to valproic acid and sodium valproate.     

Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans.

The steady-state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three-period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 h) for 6 days; cimetidine 300 mg four times daily for 6 days; and 200 mg nefazodone hydrochloride twice daily + 300 mg cimetidine four times daily for 6 days. On day 7 of each treatment, only the morning dose was administered. Serial blood samples were collected for pharmacokinetic analysis after drug administration on day 7 of each treatment; blood samples for trough levels (Cmin) to assess attainment of steady state, were also collected just prior to the morning doses on days 2-7 of each study period. Plasma samples were assayed for cimetidine, and nefazodone and its metabolites hydroxynefazodone and m-chlorophenylpiperazine by specific, validated h.p.l.c. methods. Statistical analyses of Cmin data indicated that, regardless of treatment, steady state was achieved for cimetidine by day 2 and for nefazodone and its metabolites by day 3 of multiple dosing, and that there were no significant differences in Cmin levels between treatments. When nefazodone and cimetidine were co-administered for 1 week, no change in steady-state pharmacokinetic parameters for cimetidine, nefazodone or hydroxynefazodone was observed compared with each drug dosed alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of effect of propranolol on the steady-state plasma levels of ketanserin

The effect of propranolol treatment on the steady-state plasma levels of ketanserin was evaluated in 6 patients suffering from borderline hypertension and in 2 healthy volunteers. All subjects received ketanserin 40 mg b.i.d. for 21 days. From day 8 to 14 of the study propranolol was given additionally in a dose of 80 mg bid. This dose of propranolol had to be reduced in 3 subjects because of side effects. Steady-state plasma concentrations (measured 4-6 h after the dose) of ketanserin varied from 51.0 +/- 13.6 to 67.8 +/- 13.8 ng/ml (mean +/- SEM) during the entire study period. Treatment with propranolol (plasma concentrations ranged from 45.7 +/- 15.8 to 65.7 +/- 11.4 ng/ml) did not significantly alter the plasma concentrations of ketanserin. The same was true for the minimal plasma concentrations of ketanserin measured at the end of each treatment period. Blood pressure decreased during the 21 days treatment period with ketanserin (mean systolic blood pressure decreased from 144 +/- 5 to 123 +/- 7 and diastolic from 81 +/- 3 to 72 +/- 5 mmHg). Propranolol had a slight additional hypotensive effect. Heart rate decreased during treatment with propranolol. It is concluded that simultaneous oral treatment with propranolol in doses up to 160 mg/day does not alter the first-pass metabolism and the elimination kinetics of ketanserin.     

Lack of effect of tenoxicam on dynamic responses to concurrent oral doses of glucose and glibenclamide.

1. In a single-blind, placebo controlled study the influence of tenoxicam on responses of glucose, insulin and C-peptide to oral doses of glucose and glibenclamide was examined in 16 healthy male volunteers. 2. The subjects received once daily doses of 2.5 mg glibenclamide for 12 days. From day 5 through 12 eight subjects received concomitantly 20 mg tenoxicam once daily and the remaining eight subjects received placebo. 3. On days 1, 4, 5 and 12 glibenclamide was taken with 75 g glucose and blood glucose, serum insulin and C-peptide were measured over 5 h. Plasma levels of glibenclamide and tenoxicam (where appropriate) were followed over 10 h. 4. Characteristic parameters of blood glucose and insulin and C-peptide responses did not change significantly with time (day) and there was no difference between both treatment groups. 5. Baseline insulin increased from 11.7 mu l-1 on day 1 to 15.6 mu l-1 on day 4 (P = 0.009), likewise baseline C-peptide increased from 478 pmol l-1 to 530 pmol l-1 (P = 0.05), but there was no further change in the subsequent treatment period. 6. The AUC of the glibenclamide plasma concentration-time curve did not show changes with time or differences between treatment groups. The mean (s.d.) oral clearance of tenoxicam was 2.5 (1.5) ml min-1 and appeared slightly higher than in previous studies. 7. It was concluded that tenoxicam did not affect overall glycoregulation in healthy subjects under glibenclamide steady state conditions.