Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam.

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03 mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t1/2) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t1/2 by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding.

Pharmacokinetics and clinical effects of alprazolam following single and multiple oral doses in patients with panic disorder.

The anxiolytic triazolobenzodiazepine alprazolam was administered to six male patients, aged 26 to 46 years, with panic disorder or agoraphobia (with panic attacks) to assess clinical effects and steady-state pharmacokinetics following multiple dosing at three levels: 3.0 mg/d, 6.0 mg/d, and 9.0 mg/d. Multiple-dose kinetics of alprazolam were compared with alprazolam disposition after a 1.0-mg oral dose in the same patients. Kinetic variables after the single dose were very similar to those reported previously for healthy young male volunteers. Mean values were peak plasma concentration, 19 ng/mL; time of peak, 1.33 hours after dosage; elimination half-life, 10.0 hours; total oral clearance, 1.11 mL/min/kg. During multiple dosage, mean steady-state plasma concentrations (Css) was proportional to dosing rate, and steady-state clearance was independent of dosage. Clinical improvement was rapid, with the greatest decrement in symptoms at the 3-mg/d dosage, at a mean Css of 30 ng/mL. Further improvement was not seen at 6 mg/d (Css, 62 ng/mL), or at 9 mg/d (Css, 103 ng/mL). Side effects, however, were directly related to dosage and plasma level, and increased progressively in number at the 3-, 6-, and 9-mg/d dosage levels. Thus, the disposition of alprazolam in young male patients with panic disorder is essentially identical to that in healthy male volunteers of similar age. Alprazolam clearance is independent of dose and plasma concentration up to daily doses of at least 9 mg/d, with steady-state plasma level proportional to dosing rate.

Desmethyldiazepam pharmacokinetics: studies following intravenous and oral desmethyldiazepam, oral clorazepate, and intravenous diazepam.

After single 10-mg intravenous (IV) doses of desmethyldiazepam (DMDZ) to 12 healthy human volunteers, (mean age, 62 years) blood samples were obtained over the next 14 or more days. Mean kinetic variables were volume of distribution (Vd), 90 liters; elimination half-life (t1/2), 93 hours; and clearance, 12.3 mL/min. Vd was significantly correlated with body weight (r = .73, P less than .01) and with percent ideal body weight (r = .91, P less than .001). Eleven of the same subjects also received 5- to 15-mg doses of IV diazepam (DZ). Mean kinetic variables were Vd, 180 liters; t1/2, 83 hours; and clearance, 28 mL/min. Clearances of DZ and DMDZ were significantly correlated (r = .73, P less than .02). Based on area analysis, the extent of conversion of DZ to systemic DMDZ averaged 53%. After oral administration of DMDZ in tablet form (10 mg), or of clorazepate dipotassium in capsule form (15 mg), systemic availability of DMDZ from each of the oral dosage forms was not significantly different from 100%.

Influence of route of administration on physiological availability of levodopa in dogs.

The physiological basis for the reduced levodopa bioavailability following oral administration was investigated. Four dogs received single 25-mg/kg doses of 14C-levodopa on three separate occasions in a crossover fashion via hepatoportal catheter, intravenous, and oral administrations. Plasma and urine specimens were analyzed for intact levodopa and total radioactivity. The ratios of areas under the plasma concentration-time curves following hepatoportal and intravenous adminstrations were close to unity, and the shapes of the curves were virtually identical. Following oral administration, however, significant reductions in the areas under the plasma concentration-time curves were observed. These data indicate that the physiologically impaired bioavailability of orally administered levodopa occurs almost exclusively as a result of metabolic degradation within the GI lumen and/or gut wall.

Pharmacokinetics of sulphadimethoxine in cattle.

Four healthy Angus steers received a single rapid intravenous injection of sulphadimethoxine at a dose of approximately 55 mg/kg. The elimination half-life determined from plasma concentration-time data was approximately 12-5 h, and the volume of distribution was 31-0 per cent of body weight. Animals also received sulphadimethoxine intravenously or orally at a loading dose of approximately 55 mg/kg, followed by sustaining oral doses of approximately 27-5 mg/kg at 24, 48 and 72 h. It was demonstrated that oral maintenance doses served to sustain sulphonamide plasma concentrations achieved with the loading dose.

Radioimmunoassay of atropine in plasma.

Antibodies, against atropine, were produced in rabbits immunized with atropine conjugated to bovine serum albumin. The antisera possessed a high binding affinity and were quite specific. The sensitivity of the method allowed detection of 6.25 ng of atropine per ml of plasma in a 10-microliter specimen. The method does not require an extraction procedure and can be performed using very small volumes of plasma. Plasma concentration-time profiles were determined by this method in dogs after rapid i.v. administration of atropine. Atropine declined from plasma in a biexponential fashion, exhibiting a terminal half-life of approximately 2.1 hours.

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.