Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant ...pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.
Conventional analysis of initial uptake and egress rates in isolated hepatocytes is limited in the ability to distinguish between rates of metabolite formation and egress, and to separate basolateral ...and canalicular transport processes. The present study examined the applicability of kinetic modeling in describing acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) formation and egress in hepatocytes after acute exposure to phenobarbital or p-hydroxyphenobarbital glucuronide (p-OHPBG) in vitro, or in vivo phenobarbital pretreatment. A significant pretreatment effect on AG and AS disposition was seen based on initial rates of egress. In vivo phenobarbital pretreatment decreased the initial egress rate of AG compared to vehicle pretreatment, and the initial egress rate of AS compared to all other treatments. A pharmacokinetic model incorporating AG and AS formation in hepatocytes as well as egress processes (including diffusional and active transport components) was fit to the data. Parameter estimates derived from model fits to the data showed the expected increase in acetaminophen glucuronidation and decrease in sulfation after phenobarbital pretreatment; in addition, an increase in the AG diffusional rate constant and a decrease in the AS diffusional rate constant was apparent. The excretion Vmax for AG was decreased statistically after acute phenobarbital exposure in vitro, and in vivo phenobarbital pretreatment, with a concomitant statistical increase in the Km for AG excretion. In vitro acute p-OHPBG exposure also decreased significantly the excretion Vmax for AG. These data are consistent with the hypothesis that phenobarbital-impaired biliary excretion of AG is a function of impaired canalicular transport due to the presence of p-OHPBG. They further suggest that the mechanism may not be simple competitive inhibition. This work demonstrates the utility of a kinetic modeling approach to differentiate metabolic and transport processes when analyzing data from isolated hepatocyte studies. Additional information may be gained that would not be apparent by conventional methods of analysis.
Diazepam 10 mg/2 mL iv was administered undiluted over five minutes to nine healthy men on two separate occasions. The infusion site was evaluated before and after each infusion by subject assessment ...of pain on a severity scale of zero (none) to ten (most). Blood samples were collected at 0, 5, 20, 30, 45, and 60 minutes, and periodically for 72 hours postinfusion. Diazepam plasma concentrations were determined by HPLC. Concentrations at five minutes (end of infusion) ranged from 0 to 889 ng/mL. Maximum plasma concentration (Cmax) was observed at 5 minutes for 10 treatments, at 20 minutes for 7 treatments, and at 30 minutes for 1 treatment. The observed Cmax ranged from 221 to 889 ng/mL. When time to reach peak plasma concentration (tmax) was 5 minutes, the Cmax was significantly greater than when tmax was 20 minutes (670 +/- 87 vs. 267 +/- 40 ng/mL, p less than 0.005). The area under the curve did not differ significantly between these two groups. The pain score at the end of infusion ranged from zero to five and was inversely related to the concentration at five minutes (r2 = 0.45, p = 0.002). The association between venous irritation, a low plasma concentration at the end of the infusion, and a delayed Cmax suggests that diazepam precipitated in the vein.
An improved high-performance liquid chromatographic (HPLC) method utilizing solid-phase extraction (SPE) and midbore chromatography was developed for the determination of ranitidine in human plasma. ...A mobile phase of 20 m
M K
2HPO
4-acetonitrile-triethylamine (87.9:12.0:0.1, v/v) pH 6.0 was used with a phenyl analytical column and ultraviolet detection (UV). The method demonstrated linearity from 25 to 1000 ng/ml in 500 μl of plasma with a detection limit of 10 ng/ml. The method was utilized in a pharmacokinetic study evaluating the effects of pancreatico-biliary secretions on ranitidine absorption.
The toxicokinetics of intravenously administered methanol were examined in female Sprague-Dawley rats. Animals received a single administration of 100, 500, or 2500 mg methanol/kg; the two lower ...doses were administered as a bolus, while the high dose was administered over 1.5 min. A small (approximately 3%) but statistically insignificant (p > 0.1) degree of transpulmonary methanol extraction, expressed as the fractional arterial-venous difference in concentration, was observed after administration of 250 mg methanol/kg. The elimination of methanol from the systemic circulation was markedly nonlinear, suggestive of a significant capacity-limited route of elimination. A single set of kinetic parameters (apparent distributional volume of the central compartment Vc, intercompartmental transfer rate constants k12 and k21, and Vmax and Km for elimination) described the blood methanol concentration-time data from rats receiving the 100 and 500 mg/kg doses. Blood methanol concentrations declined much more rapidly in animals receiving the 2500 mg/kg dose than would be predicted from the kinetic parameters derived from the other two experimental groups. The data from the 2500 mg/kg group could be described adequately by a kinetic model incorporating parallel first-order and saturable elimination processes. A portion of this apparent linear elimination pathway was due to renal excretion of the unchanged alcohol. The presence of both linear and nonlinear elimination pathways for methanol may have implications regarding high-dose to low-dose toxicologic extrapolations.
