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Biomedical subjects

J C Fleishaker

Publications and source records attributed to J C Fleishaker.

At least 37 records · Page 2Linked to original sources
PubMed1998

Biotransformation of tirilazad in human: 4. effect of finasteride on tirilazad clearance and reduced metabolite formation.

The effect of oral finasteride, an inhibitor of 5alpha-reductase, on the clearance of tirilazad, a membrane lipid peroxidation inhibitor, was assessed in eight healthy men who received: 1) 10 mg/kg tirilazad mesylate solution orally on the 7th day of a 10-day regimen of 5 mg finasteride once daily, 2) 10 mg/kg tirilazad mesylate orally, 3) 2 mg/kg tirilazad mesylate i.v. on the 7th day of a 10-day regimen of 5 mg finasteride once daily and 4) 2 mg/kg tirilazad mesylate i.v., in a four-way cross-over design. Plasma concentrations of tirilazad and its active reduced metabolites (U-89678 and U-87999) were measured by liquid chromatography with tandem mass spectrometry (LC-MS-MS). Finasteride increased mean tirilazad areas under the curve by 21 and 29% for i.v. and p.o. tirilazad, respectively. Mean U-89678 areas under the curve were decreased 92 and 75% by finasteride administration with i.v. and p.o. tirilazad, respectively, and decreases of 94 and 85% in mean U-87999 area under the curve values were observed. These differences were statistically significant. These results indicate that finasteride inhibits the metabolism of tirilazad to U-89678. However, this inhibition has only a moderate effect on the overall clearance of tirilazad. These results thus confirm earlier in vitro work that showed that tirilazad is predominantly metabolized by CYP3A4. Although the major circulating metabolites of tirilazad are formed via reduction, this represents a minor route of tirilazad elimination in man.

Adolescent↗
PubMed1997

Pharmacokinetics and psychomotor performance of alprazolam: concentration-effect relationship.

The relationship between the pharmacokinetics of alprazolam and dose and the relationship between the concentration of alprazolam and psychomotor performance in healthy male volunteers were investigated in this double-blind, placebo-controlled, modified crossover study. Twenty-four volunteers received placebo in Phase I and then received single 2-mg, 4-mg, 8-mg, and 10-mg doses of a sustained-release formulation in Phases II through V, according to, a crossover design. Blood samples were collected at several times throughout each phase to 48 hours after the dose; the harvested plasma was assayed for concentrations of alprazolam, 4-hydroxyalprazolam, and alpha-hydroxyalprazolam by high-performance liquid chromatography. Sedation was rated at each blood-sampling time and psychomotor performance tests, consisting of digit-symbol substitution and card-sorting tasks, were conducted at several times after each dose. Area under the concentration-time curve and peak concentration for alprazolam increased proportionally with each higher dose; clearance did not differ significantly between treatments. The concentrations of 4-hydroxyalprazolam and alpha-hydroxyalprazolam increased proportionally with dose and the combined plasma concentration of the metabolites were less than 15% of unchanged concentrations of alprazolam for all doses. Maximum sedation increased with each increase in dose up to 8 mg, and psychomotor performance decreased with each increase in dose. Performance versus concentration curves for alprazolam exhibited a clockwise hysteresis loop in contrast to the counterclockwise hystereses previously reported for both intravenous and oral doses of immediate-release tablets. Data through 6 hours after dose were well described by a sigmoid Emax model. Alprazolam exhibits linear pharmacokinetics after single oral doses of sustained-release tablets between 2 mg and 10 mg. Reversal of the concentration-effect curve to a clockwise loop suggests the counterclockwise hystereses of rapidly absorbed doses was caused by the differing distribution rates into the systemic circulation and effect site and not by metabolite activity.

Adult↗
PubMed1997

The pharmacokinetics and pharmacodynamics of adinazolam: multi-ethnic comparisons.

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD), its major active metabolite, were compared in 39 healthy male volunteers (13 Asian, 12 Caucasian and 14 African-American). In a four-way, double-blind crossover design, subjects were administered (1) 30 mg oral adinazolam mesylate SR tablets, (2) 10 mg parenteral (i.v.) adinazolam mesylate, (3) 30 mg i.v. NDMAD and (4) placebo. Venous blood samples were collected at specific time intervals after drug administration and assayed for adinazolam and NDMAD concentrations. Sedation was rated at the time of each blood draw according to the Nurse-Rated Sedation Scale, and the digit-symbol substitution test was administered to evaluate psychomotor performance. After i.v. administration of adinazolam, Asians manifested significantly higher Cmax, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after i.v. NDMAD Asians had significantly higher NDMAD Cmax and AUC than Caucasians and African-Americans. Most of these differences remained statistically significant after controlling for body surface area. With PO adinazolam, Asians also manifested substantially higher Cmax, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of Cmax, these differences did not reach statistical significance. These results are in accordance with previous observations for ethnic-related differences in drug pharmacokinetics. In contrast, pharmacodynamic differences were not noted among the three study groups.

Adult↗
PubMed1997

Pharmacokinetics of tirilazad and U-89678, an active, reduced metabolite, following acute head trauma in adults.

The pharmacokinetics of tirilazad and U-89678 (an active metabolite) were evaluated in 55 adults (48 males, 7 females) with moderate or severe head injury who received 10.0 mg/kg/day tirilazad mesylate for 5 days. Trough plasma samples were obtained daily; serial plasma samples were obtained over one dosing interval on day 5. Plasma tirilazad and U-89678 were quantified by HPLC. Sixty-two percent of the subjects received concomitant anticonvulsants, of which 91% received phenytoin. Plasma tirilazad and U-89678 concentrations in head-injured patients were similar to or lower than those observed in healthy volunteers. Sufficient data were available to calculate pharmacokinetic parameters for day 5 in 26 patients; 11 received no anticonvulsants. The AUC0-6 (are under the concentration-time curve at 0-6 h) for tirilazad mesylate on day 5 in patients receiving anticonvulsants (median = 4972 ng h/mL) differed significantly from that in patients not receiving anticonvulsants (median = 9704 ng h/mL) (p = 0.0051). Similarly, the AUC0-6 of U-89678 in patients receiving anticonvulsants (median = 561 ng h/mL) was significantly different from that in patients who were not (median = 2494 ng h/mL) (p = 0.0016). Comparison of pharmacokinetic data from patients not receiving anticonvulsants to historical data in healthy volunteers suggests that head injury has little effect on tirilazad pharmacokinetics within 5 days of injury. These results suggest that the major factor affecting tirilazad pharmacokinetics in head-injured patients is concomitant use of enzyme-inducing anticonvulsants.

Adult↗
PubMed1997

Pharmacokinetics of tirilazad in healthy male subjects at doses above 6 mg/kg/day.

The dose proportionality of tirilazad pharmacokinetics at dosages above 6.0 mg/kg/day were assessed in 18 healthy male volunteers between the ages of 19 and 46 years. Subjects were randomized to receive either 1.5 mg/kg, 3.0 mg/kg, or 4.0 mg/kg tirilazad mesylate every 6 hours for 29 doses (daily doses of 6.0, 12.0, and 16.0 mg/kg/day for 7 days). Each drug dose was administered intravenously over 10 minutes. Plasma tirilazad, U-89678, and U-87999 (active reduced metabolites) were quantified by HPLC. Two subjects in the high dose group withdrew before the end of the study. Following the first dose of tirilazad, dose-corrected pharmacokinetic parameters for all 3 compounds did not differ significantly among dose groups. After the final tirilazad the mean half-life of tirilazad was approximately 80 hours. Mean apparent tirilazad clearance did not differ significantly among groups. Mean U-89678 AUC0-6 following the last tirilazad dose did not differ significantly between the 6.0 and 12.0 mg/kg/day doses, but the value for the 16.0 mg/kg dose was higher than values from both lower doses (p = 0.044 and 0.056, respectively). Similar results were obtained for U-87999. The dose effects observed for the pharmacokinetics of these 2 metabolites may have been a function of intersubject variability. When combined with previous data concerning the dose proportionally of tirilazad pharmacokinetics at doses less than 6.0 mg/kg/day, the data from the present study suggest that the pharmacokinetics of tirilazad are approximately linear over a dosage range of 1.0-16.0 mg/kg/day. Due to the inability to assess the plasma protein binding of tirilazad and its reduced metabolites, the clinical significance of the departure from linearity of the pharmacokinetics of U-89678 and U-87999 cannot be directly assessed. Further study at higher doses will be needed to address this issue.

Adult↗
PubMed1996

Pharmacokinetics of tirilazad and U-89678 in ischemic stroke patients receiving a loading regimen and maintenance regimen of 10 mg/kg/day of tirilazad.

The pharmacokinetics of tirilazad mesylate and its active reduced metabolite, U-89678, were evaluated in ischemic stroke patients receiving 2.5 mg/kg tirilazad every 3 hours for the first 12 hours of dosing followed by 2.5 mg/kg every 6 hours for a total of 22 doses (5 days). Trough and serial samples drawn during the 6 hours after administration of the last dose were analyzed for plasma levels of tirilazad and U-89678 by means of high-performance liquid chromatography. Complete concentration-time profiles were available for 20 patients, including 12 men (mean age, 68.0 years) and 8 women (mean age, 75.0 years). Trough concentrations of tirilazad and U-89678 were consistent with the loading regimen used. The mean area under the concentration-time curve from time 0 to 6 hours (AUC0-6) of tirilazad was 8181 +/- 2398 ng.hr/mL in men and 8135 +/- 3671 ng.hr/mL in women. The mean AUC0-6 of U-89678 was 2761 +/- 1834 ng.hr/mL in men and 1477 +/- 903 ng.hr/mL in women. These results show that gender has a modest effect on the pharmacokinetics of U-89678 but little effect on the pharmacokinetics of tirilazad in elderly ischemic stroke patients. These observations are consistent with previous findings in healthy young and elderly subjects.

Aged↗
PubMed1996

Gender does not affect the degree of induction of tirilazad clearance by phenobarbital.

OBJECTIVE: Tirilazad mesylate is a membrane lipid peroxidation inhibitor being evaluated for the treatment of patients with subarachnoid haemorrhage (SAH); phenobarbital may be administered to these patients for seizure prophylaxis. Therefore, the effect of phenobarbital on tirilazad mesylate pharmacokinetics was assessed in 15 healthy volunteers (7M, 8F). METHODS: Subjects received 100 mg phenobarbital orally daily for 8 days in one phase of a two-way crossover study. In both phases, 1.5 mg.kg-1 tirilazed mesylate was administered (as a 10 minute IV infusion) every 6 hours for 29 doses. Three weeks separated study phases. Tirilazad mesylate and U-89678 (an active metabolite) in plasma were quantified by HPLC. RESULTS: Phenobarbital had no effect on the first dose pharmacokinetics of tirilazad or U-89678. After the final dose, clearance for tirilazad was increased 25% in males and 29% in females receiving phenobarbital + tirilazad versus tirilazad mesylate alone. These differences were statistically significant, and the degree of induction was not significantly different between genders. AUC(zero)-6 for U-89678 after the last tirilazad mesylate dose was reduced 51% in males and 69% in females. The decreases were statistically significant, and there was no gender by treatment interaction. CONCLUSION: The results show that phenobarbital induces metabolism of tirilazad and U-89678 similarly in both men and women. Lower levels of tirilazad and U-89678 in SAH patients receiving phenobarbital may adversely impact clinical response.

Adult↗
PubMed1996

Comparison of the pharmacokinetics of tirilazad mesylate in healthy volunteers and stable subjects with mild liver cirrhosis.

OBJECTIVE: The pharmacokinetics of tirilazad mesylate and an active reduced metabolite, U89678, were studied in 7 volunteers with mild cirrhosis of the liver, and seven age, sex, weight and smoking status matched healthy normal volunteers. Subjects received a single intravenous infusion of 2.0 mg.kg-1 tirilazad mesylate over 10 min. RESULTS: Mean tirilazad AUCzero-infinity was 8.83 mumol h.l-1 and 18.6 mumol h.l-1 in healthy volunteers and cirrhotic subjects, respectively. Mean tirilazad clearance in cirrhotics (12.7 l.h-1) was approximately 2.1 fold lower than in healthy volunteers (27.8 l.h-1). The differences were statistically significant. Mean U-89678 AUCzero-infinity in cirrhotic subjects (3.88 mumol h.l-1) was 2.5 fold higher than in healthy controls (1.53 mumol h.l-1), but the difference was marginally significant. CONCLUSION: These results indicate that clearance of both tirilazad mesylate and U89678 is decreased in subjects with hepatic impairment. This observation may be attributed either to decreases in liver blood flow and/or intrinsic clearance. The results of this study thus suggest that increased monitoring and or a reduction in tirilazad dosing may be necessary in patients with hepatic impairment.

Antioxidants↗
PubMed1996

Biotransformation of tirilazad in human: 2. Effect of ketoconazole on tirilazad clearance and oral bioavailability.

The effect of ketoconazole, a CYP3A inhibitor, on the oral bioavailability of tirilazad mesylate was assessed in 12 healthy subjects, who received the following treatments in a crossover design: a) 10 mg/kg tirilazad mesylate solution orally on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily, b) 10 mg/kg tirilazad mesylate solution orally, c) 2 mg/kg i.v. tirilazad mesylate solution on the fourth day of a 7-day regimen of 200 mg ketoconazole once daily and d) 2mg/kg i.v. tirilazad mesylate solution. Plasma concentrations of tirilazad mesylate and its active reduced metabolites (U-89678 and U-87999) were measured by high-performance liquid chromatography. Urinary ratios of 6 beta-hydroxycortisol to cortisol (6 beta-OHC/C) were measured as an index of hepatic CYP3A activity. Ketoconazole increased mean tirilazad mesylate area under the curve (AUC) values by 67% and 309% for i.v. and oral administration, respectively. Mean AUC values for U-89678 were increased 472% and 720% by ketoconazole coadministration with i.v. and oral tirilazad, respectively, whereas increases of > 10-fold in mean U-87999 AUC values were observed. These differences were statistically significant. These results indicate that ketoconazole inhibits the metabolism of these three compounds, which suggests that all of the compounds are substrates for CYP3A. Urinary 6 beta-OHC/C ratios did not reflect this level of effect of ketoconazole on CYP3A; this probe may not be useful for assessing the effect of CYP3A inhibitors. The absolute bioavailability of oral tirilazad was 8.7 +/- 4.8%; ketoconazole increased the bioavailability to 20.9 +/- 6.5%. Ketoconazole increased tirilazad mesylate bioavailability by decreasing the first-pass liver and gut wall metabolism of tirilazad mesylate to similar degrees.

Adult↗
PubMed1995

Phenytoin causes a rapid increase in 6 beta-hydroxycortisol urinary excretion in humans--a putative measure of CYP3A induction.

This study was conducted in eight healthy volunteers to assess the time course of induction of cytochrome P-450 by phenytoin. subjects received 200 mg of phenytoin every 8 h for 11 doses and 100 mg every 8 h for 8 doses. Trough concentrations of phenytoin in plasma were measured by HPLC. Urine samples were collected between 08:00 and 12:00 on days -1, 1, 2, 3, 4, 5, and 7. Urinary concentrations of 6 beta-hydroxycortisol (6 beta-OHC) and cortisol (C) were determined by HPLC and were reported as a ratio (6 beta-OHC/C); this ratio is a marker for the 3A isozyme family of cytochrome P-450 (CYP3A). Mean plasma phenytoin concentrations on day 7 were 15.4 +/- 7.20 micrograms/mL. Mean 6 beta-OHC/C ratios increased by a factor of 2.37 from baseline during the course of the study. Values for the ratios on days 4, 5, and 7 were significantly higher than baseline by Dunnett's test (one-sided) (p < 0.05); the day 3 value was borderline statistically significant. These results show that phenytoin rapidly induces the activity of the CYP3A family of isozymes, with effects apparent within 48 h after the initiation of phenytoin therapy.

Adolescent↗
PubMed1995

Comparison of the spectrum of cognitive effects of alprazolam and adinazolam after single doses in healthy subjects.

Single doses of alprazolam (0, 0.5, 1.5 mg) or adinazolam mesylate sustained release tablets (SR) (0, 15, 45 mg) were administered to separate groups of 12 healthy men in a crossover design. Psychomotor performance was assessed by digit symbol substitution (DSST), and memory was assessed using a test battery which reflects various aspects of memory, including attention/working memory, explicit memory (recall of categorically related words), semantic memory (fragmented picture recognition, generation of category exemplars), and implicit memory (time saved in resolving fragmented pictures on the second exposure). Maximal psychomotor performance and memory decrements for the highest active doses were significantly different from placebo for all tasks at some time after dosing. The maximum decrement in DSST was not significantly different between drugs at the high dose (P = 0.288). Maximum attention/working memory decrements were significantly different between the high doses of the active compounds (P = 0.031), and the difference in maximum category recall decrement was marginally significant (P = 0.067). Access to knowledge memory was not significantly altered by these drugs; these results are similar to those obtained for other benzodiazepines. Both drugs exhibited slight effects on implicit memory. The results suggest that the sedative and memory effects of these triazolobenzodiazepines may not be closely related and suggest that adinazolam has a somewhat different spectrum of cognitive effects relative to alprazolam.

Administration, Oral↗
PubMed1995

Alprazolam absorption kinetics affects abuse liability.

OBJECTIVE: To evaluate the behavioral, subjective, and reinforcing effects of immediate-release (IR) alprazolam and extended-release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability. METHODS: Fourteen healthy men with histories of sedative abuse participated as subjects in a double-blind crossover study. All subjects received placebo, 1 and 2 mg immediate-release alprazolam, and 2 and 3 mg extended-release alprazolam in random order. Behavioral performance, subjective effects, and alprazolam plasma concentrations were assessed repeatedly 1/2 hour before and 1/2, 1, 3, 5, 7, 9, 12, and 24 hours after drug administration. RESULTS: Mean peak alprazolam plasma concentrations occurred 1.7 and 9.2 hours after immediate-release alprazolam and extended-release alprazolam, respectively. Compared to placebo, 2 mg immediate-release alprazolam impaired all measures of psychomotor and cognitive performance (Digit Symbol Substitution Test), motor coordination (circular lights and balance), and memory (digit entry and recall); 2 mg extended-release alprazolam did not affect any of these measures and 3 mg extended-release alprazolam impaired circular lights only. Immediate-release alprazolam, 2 mg, increased all six measures of positive drug effects (e.g., ratings of liking or good effects); none of these measures were increased by 2 mg extended-release alprazolam and only three of the six measures were increased by 3 mg extended-release alprazolam. A drug versus money multiple-choice procedure designed to assess the relative reinforcing effects of each condition was administered 24 hour after the drug. The amount of money subjects were willing to "pay" to take the drug was significantly greater than placebo for both doses of immediate-release alprazolam but for neither dose of extended-release alprazolam. CONCLUSIONS: These data indicate that extended-release alprazolam has less potential for abuse than immediate-release alprazolam.

Adult↗
PubMed1995

Studies with [11C]alprazolam: an agonist for the benzodiazepine receptor.

We have built a system for the synthesis of high specific activity carbon-11 alprazolam (Xanax), a high affinity agonist for the benzodiazepine receptor. The system produces 30-40 mCi of the compound with a specific activity of > 12,000 Ci per millimole. Using this compound we have performed PET studies on 6 normal subjects and studied the cerebral influx and efflux of the compound. The uptake in the brain was low, approx. 1% of the administered dose. However, the levels of the compound in the circulation at early time points are heavily affected by the specific activity of the tracer, i.e. when pharmacologically active doses are used as blocking doses the concentration of radioactive material is higher in the circulation and more material enters the brain. We attribute this to a depot effect where the compound is trapped in saturatable sites in an organ, probably the lungs, and is slowly released over time. In the presence of blocking doses of agonist, the compound washes out of the brain more quickly suggesting that some blockade of the receptors is occurring. However, the pharmacological activity of the compound does not permit the administration of enough material to ensure complete receptor blockade. The compound shows definite signs of acting as a receptor binding ligand but the unusual pharmacokinetics complicate the interpretation of the data.

Alprazolam↗
PubMed1994

The lack of effect of smoking on the pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam.

The pharmacokinetics and pharmacodynamics of adinazolam and N-demethyladinazolam (NDMAD) were evaluated in twelve healthy non-smokers (NS) and twelve smokers (S, > or = 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained-release tablets in an open-label, parallel-group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8 +/- 25.8 versus 48.2 +/- 14.01 h-1) or peak adinazolam plasma concentrations (Cmax) (93.3 +/- 31.8 versus 90.4 +/- 18.0 ng ml-1) between groups. NDMAD AUC (2541 +/- 457 versus 2798 +/- 447 ng h ml-1) and Cmax (173 +/- 30.3 versus 175 +/- 26.9 ng ml-1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non-smokers (8.7 +/- 0.7 versus 10.7 +/- 2.71 h-1; p < 0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol-digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly decrease renal clearance of NDMAD.

Adult↗
PubMed1994

Lack of a pharmacokinetic/pharmacodynamic interaction between nimodipine and tirilazad mesylate in healthy volunteers.

The potential interaction between tirilazad mesylate, a membrane lipid peroxidation inhibitor, and nimodipine, a calcium-channel antagonist, was assessed in 12 healthy male volunteers. Subjects received 60 mg nimodipine orally, 2.0 mg/kg tirilazad mesylate as a 10-minute intravenous infusion, and a combination of the two treatments according to a balanced 3-way crossover design. No significant effects of nimodipine on tirilazad mesylate pharmacokinetic parameters were observed (P > .05). Values for tirilazad mesylate clearance (34.9 +/- 8.96 L/hr) and half-life (29 +/- 7.83 hr) were consistent with previous studies. Nimodipine pharmacokinetic parameters exhibited substantial variability, and mean AUC was approximately 25% below the range of previously published values. However, no significant differences in nimodipine pharmacokinetics were observed between treatments. Nimodipine administration increased heart rate slightly without a change in blood pressure, which was not observed after tirilazad administration and was not altered when tirilazad and nimodipine were coadministered. Thus, no significant interaction between tirilazad mesylate and nimodipine is detectable after single-dose administration.

Administration, Oral↗
PubMed1994

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine.

We have assessed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzo-diazepine. Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1-3, 100 mg on days 4-10) (n = 20), 1 mg of alprazolam four times daily for four days (days 7-10 of the study period) (n = 20), or a combination of the two (n = 20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10. Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration. The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam. The dosage of alprazolam should be reduced during co-administration with fluvoxamine.

Adult↗
PubMed1994

Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans.

The effects of probenecid (2 gm) on the pharmacokinetics, pharmacodynamics, and uricosuric effects of adinazolam and N-desmethyladinazolam were assessed after single dose administration of adinazolam mesylate sustained-release tablets (60 mg) in a randomized, four-way crossover, double-blind study involving 16 healthy male volunteers. Probenecid decreased adinazolam oral clearance, renal N-desmethyladinazolam clearance, and the amount of N-desmethyladinazolam excreted in the urine. Probenecid increased the N-desmethyladinazolam/adinazolam AUC ratio, adinazolam maximum concentration (Cmax), N-desmethyladinazolam Cmax, and N-desmethyladinazolam time to reach Cmax. Uric acid renal clearance was increased significantly by adinazolam or probenecid administration compared with placebo; however, coadministration of adinazolam plus probenecid had no additive effect on uric acid clearance. Psychomotor performance was decreased in the adinazolam plus probenecid treatment compared with the adinazolam treatment. Probenecid potentiated the psychomotor effects of adinazolam after coadministration of the compounds, predominantly because of alterations in N-desmethyladinazolam pharmacokinetics. Therefore the adinazolam dose may need to be reduced when coadministered with probenecid.

Administration, Oral↗