Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.     

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 (IV) adinazolam mesylate, (3) 30 mg IV 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 IV administration of adinazolam, Asians manifested significantly higher C_max, larger AUC and lower CL of both adinazolam and NDMAD than their Caucasian and African-American counterparts. Likewise, after IV NDMAD Asians had significantly higher NDMAD C_max 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 C_max, larger AUC and lower CL for both adinazolam and NDMAD; however, with the exception of C_max, 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. Received: 19 June 1996/Final version: 17 September 1996     

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg oral doses of its mesylate salt in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam were studied in 15 normal, healthy, non-obse volunteers. Placebo capsules and capsules containing 20, 40, and 60 mg adinazolam mesylate were administered as single oral doses in a randomized, 4-way crossover design. Plasma concentrations of adinazolam and mono-N-desmethyladinazolam (NDMAD) were determined by HPLC. Psychomotor performance and memory tests were performed and the degree of sedation assessed at designated times following drug administration. Adinazolam and NDMAD pharmacokinetics were linear throughout the dosage range studied. The ratio of NDMAD to adinazolam area under the curve was approximately 4:1. Dose-related decrements in psychomotor performance and memory were observed up to 8h after dosing (P<0.025 in all cases). Psychomotor performance decrements correlated more closely with NDMAD plasma concentrations than with adinazolam concentrations. These results suggest that NDMAD is responsible for a significant degree of the sedative and psychomotor effects observed after the administration of adinazolam.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.     

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, ? 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 (C_max) (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 C_max (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.     

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

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.     

Dose-dependent pharmacokinetics of a new reversible proton pump inhibitor, DBM-819, after intravenous and oral administration to rats: hepatic first-pass effect.

The dose-dependent pharmacokinetic parameters of DBM-819 were evaluated after intravenous (5, 10 and 20 mg/kg) and oral (10, 20 and 50 mg/kg) administrations of the drug to rats. The hepatic first-pass effect was also measured after intravenous and intraportal administrations of the drug, 10 mg/kg, to rats. After intravenous administration, the dose-normalized (based on 5 mg/kg) area under the plasma concentration-time curve from time zero to time infinity, AUC, at 20 mg/kg (27.0 and 45.8 microg min/ml) was significantly greater than that at 5 mg/kg due to saturable metabolism. After oral administration, the dose-normalized (based on 10 mg/kg) AUC(0-12 h) at 50 mg/kg (25.1, 18.3 and 49.2 microg min/ml) was significantly greater than those at 10 and 20 mg/kg again due to saturable metabolism. After oral administration of DBM-819, 10 mg/kg, 2.86% of oral dose was not absorbed and the extent of absolute oral bioavailability (F) was estimated to be 46.7%. After intraportal administration of DBM-819, 10 mg/kg, the AUC was 51.9% of intravenous administration, suggesting that approximately 48.1% was eliminated by liver (hepatic first-pass effect). The considerable hepatic first-pass effect of DBM-819 was also supported by significantly greater AUC of M3 (3.70 and 6.86 microg min/ml), a metabolite of DBM-819, after intraportal administration. The AUCs of DBM-819 were not significantly different (comparable) between intraportal and oral administrations of the drug, 10 mg/kg, suggesting that gastrointestinal first-pass effect of DBM-819 was almost negligible in rats. At 10 mg/kg oral dose of DBM-819, the hepatic first-pass effect was approximately 48.1%, F was approximately 46.7 and 2.86% was not absorbed from gastrointestinal tract in rats.     

Evaluation of brain-targeting for the nasal delivery of ergoloid mesylate by the microdialysis method in rats.

The aim of this study was to quantify the nasal delivery of ergoloid mesylate (EM) to the brain by comparing cerebrospinal fluid (CSF) and plasma EM levels after nasal administration at a dose of 4 mg/kg with those after intravenous administration. Following nasal delivery, EM reached a Cmax value (mean+/-SD) in plasma of 348.41+/-19.47 ng/ml and in CSF of 87.35+/-6.37 ng/ml after 107 and 20 min, respectively, while after intravenous injection, EM reached a Cmax value (mean+/-S.D.) in CSF of 54.81+/-4.92 ng/ml at 60 min and the Cmax in plasma was 1255.51+/-133.59 ng/ml. The AUC(CSF)/AUC plasma ratio (0.48+/-0.05) after intranasal delivery differed greatly from the ratio (0.14+/-0.04) observed after intravenous injection (P<0.05). The further analyzed data demonstrated a statistically significant distribution advantage of EM to the brain via the nasal route, and further suggesting that nasal administration can be a promising alternative for EM that undergoes first-pass metabolism following oral administration.     

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.     

Comparison of adinazolam pharmacokinetics and effects in healthy and cirrhotic subjects

The pharmacokinetics and pharmacodynamics of adinazolam were investigated in six patients with cirrhosis and six sex-matched control subjects. These subjects received a single 30-mg oral dose of adinazolam mesylate. Serial blood samples were collected for 24 hours after drug administration. Plasma was assayed for adinazolam and mono-desmethyl-adinazolam (NDMAD) concentrations by a specific HPLC technique. Pharmacokinetic parameters were estimated by noncompartmental methods. Psychomotor effects of adinazolam were assessed using a digit-symbol substitution test (DSST) and aiming test (AIM). Memory effects were assessed by a modification of the Randt memory test (MEM); sedation was assessed using an observer-rated scale. Differences in pharmacokinetics of the parent drug were noted: adinazolam oral clearance was lower in patients with cirrhosis (35.0 +/- 27.9 L/hr) than in normal subjects (73.7 +/- 22.1 L/hr; P = .024); Kel was significantly lower in patients with cirrhosis (.126 +/- .084 vs. .278 +/- .070; P = .007), whereas the mean t1/2 in patients with cirrhosis was 7.70 hours as compared with 2.67 hours in normal subjects. Cmax was higher in the group with cirrhosis (266 +/- 95.5 vs. 153 +/- 29.3 ng/mL; P = .019). For NDMAD, Kel was lower in cirrhotic subjects and resulted in a prolonged t1/2 in cirrhotic subjects compared with normal subjects (6.70 vs. 3.79 hr; P = .0152). NDMAD AUC tended to be higher in cirrhotic subjects (1515 +/- 254 vs. 1162 +/- 254 ng.hr/mL; P = .064). No significant differences were noted in psychomotor performance, memory, or sedation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic and intestinal first-pass effects of oltipraz in rats

It was reported that the mean value of the extent of absolute oral bioavailability (F) of oltipraz at a dose of 20 mg/kg was 41.2% and only 2.68% of the oral dose was unabsorbed from the gastrointestinal tract in rats. Hence, the low F in rats could be due to considerable first-pass (gastric, intestinal and hepatic) effects. Hence, the first-pass effects of oltipraz were measured after intravenous, intraportal, intragastric and intraduodenal administration of the drug at a dose of 20 mg/kg to rats. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) values between intragastric and intraduodenal administration (213 and 212 microg min/ml) in rats were almost similar, but the values were significantly smaller than that after intraportal administration (316 microg min/ml) in rats, indicating that gastric first-pass effect was almost negligible (due to negligible absorption of oltipraz from rat stomach), but the intestinal first-pass effect of oltipraz was considerable, approximately 32% of the oral dose. The hepatic first-pass effect of oltipraz was approximately 40% based on AUC values between intravenous and intraportal administration (319 versus 536 microg min/ml). Since approximately 65% of the oral oltipraz was absorbed into the portal vein, the value of 40% was equivalent to 25% of the oral dose. The low F of oltipraz in rats was mainly due to considerable hepatic and intestinal first-pass effects.     

Intravenous pharmacokinetics and absolute oral bioavailability of dolasetron in healthy volunteers: part 1

In this first part of a two-part investigation, the intravenous dose proportionality of dolasetron mesylate, a 5-HT3 receptor antagonist, and the absolute bioavailability of oral dolasetron mesylate were investigated. In an open-label, randomized, four-way crossover design, 24 healthy men between the ages of 19 and 45 years received the following doses: 50, 100, or 200 mg dolasetron mesylate administered by 10-min intravenous infusion or 200 mg dolasetron mesylate solution administered orally. Serial blood and urine samples were collected for 48 h after dosing. Following intravenous administration, dolasetron was rapidly eliminated from plasma, with a mean elimination half-life (t1/2) of less than 10 min. Dolasetron was rarely detected in plasma after oral administration of the 200 mg dose. Hydrodolasetron, the active primary metabolite of dolasetron, appeared rapidly in plasma following both oral and intravenous administration of dolasetron mesylate, with a mean time to maximum concentration (t(max)) of less than 1 h. The mean t1/2 of hydrodolasetron ranged from 6.6-8.8 h. The plasma area under the concentration-time curve (AUC0-infinity)) for both dolasetron and hydrodolasetron increased proportionally with dose over the intravenous dose range of 50-200 mg dolasetron mesylate. Approximately 29-33%) and 22% of the dose was excreted in urine as hydrodolasetron following intravenous and oral administration of dolasetron, respectively. For dolasetron as well as hydrodolasetron, mean systemic clearance (C1), volume of distribution (Vd), and t1/2 were similar at each dolasetron dose. The mean 'apparent' bioavailability of dolasetron calculated using plasma concentrations of hydrodolasetron was 76%. The R(+) enantiomer of hydrodolasetron represented the majority of drug in plasma (> 75%) and urine (> 86%). Dolasetron was well tolerated following both oral and intravenous administration.     

Dose-independent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage,KR-31543, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous (iv) and oral (po) administration and first-pass effects after iv, intraportal, intragastric, and intraduodenal administration in rats. After iv (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose independent. The extent of absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F value could be due to the hepatic, gastric, and/or intestinal first-pass effects. After iv administration of three doses, the total body clearances were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect in the heart and lung in rats. The areas under the plasma concentration-time curves from time zero to time infinity (AUCs) were not significantly different between intragastric and intraduodenal administration of KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543 was almost negligible in rats. However, the values were significantly smaller (305 and 318 microg x min/mL) than that after intraportal administration (494 microg x min/mL), indicating a considerable intestinal first-pass effect of KR-31543 in rats; that is, approximately 40% of the oral dose. Approximately 50% of KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on iv and intraportal administration (the value, 50%, was equivalent to approximately 30% of the oral dose). The low F value of KR-31543 after oral administration of 20 mg/kg to rats was mainly due to considerable intestinal (approximately 40%) and hepatic (approximately 30%) first-pass effects.     

Rectal bioavailability of 6-mercaptopurine in children with acute lymphoblastic leukaemia: partial avoidance of “first-pass” metabolism

Summary Plasma levels and the area under the plasma concentration-time curve (AUC) values of 6-mercaptopurine (6-MP) were determined in a balanced crossover study of oral (powder) and rectal (macrogol suppository) administration to 5 children with acute lymphoblastic leukaemia (ALL). The AUC (538.6 ng · h · ml^–1) after the rectal dose of 30 mg/m² was approximately 1.5-times of that (365.5 ng · h · ml^–1) after the oral dose of 87.5 mg/m². The coefficients of variation of interindividual variability of the AUCs were 21.5% and 32.3%, respectively. The relative bioavailability of the macrogol suppository compared to the powder was approximately 4.39. These findings indicate that rectal administration of 6-MP could avoid the first-pass effect of this drug in the alimentary canal and/or liver, resulting in a large AUC of 6-MP, and so could reduce interindividual variability in plasma 6-MP concentrations. Rectal administration of 6-MP may be more effective than empirical oral dosing for the treatment of children with ALL, especially for patients with nausea and/or vomiting.A preliminary account of this work was presented at the 19th Annual Meeting International Society for Experimental Haematology, Seattle, Washington, 26–30 August 1990     

The Bioavailability and Nonlinear Clearance of (–)-Carbovir in the Rat

The pharmacokinetics and bioavailability of (±)-carbovir, a carbocyclic nucleoside active against human immunodeficiency virus, have been described previously. To determine the bioavailability of (–)-carbovir, the biologically active enantiomer, four male Sprague–Dawley rats received 18 mg/kg of (–)-carbovir through the jugular vein and 54 mg/kg orally. Following the pilot studies, five rats were randomly assigned to receive (–)-carbovir in a three-way crossover design as either a single 18-mg/kg iv bolus, a single 54-mg/kg oral dose, or a single iv infusion of 18 mg/kg to achieve a target steady-state concentration (C _ss) of 1 µg/ml, the peak concentration after an oral dose. Blood and urine samples were analyzed by an improved ion-paired reversed-phase HPLC method with fluorescence detection. Blood concentrations of (–)-carbovir declined in a biphasic manner after the iv bolus dose. The terminal half-life was 116 and 106 min after the iv bolus and oral dose, respectively. The blood/plasma distribution ratio was approximately 1.0 in the range of 1 to 10 µg/ml of (–)-carbovir in blood. The free fraction in serum was concentration dependent. Significant differences in the renal, nonrenal, and total-body clearances after the iv bolus and iv infusion suggested nonlinear elimination of (–)-carbovir. The oral bioavailabilities derived from blood data were significantly different when the iv bolus was used as a reference rather than the iv infusion. However, the bioavailabilities were not significantly different when the total urinary excretion of unchanged (–)-carbovir after iv bolus or infusion was used as a reference. Concomitant saturation of renal and nonrenal clearances might explain these findings. The oral bioavailability was about 20% at concentrations approximating 1 µg/ml in blood.     

N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10–50 mg oral doses in healthy volunteers

Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-desmethyladinazolam pharmacokinetics were dose independent over this range. Doserelated performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC₅₀ of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.     

Pharmacokinetics of the dimethylheptyl homolog of cannabidiol in dogs

Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that a dimethylheptyl homolog (DMH) of CBD is more active as an anticonvulsant than is the naturally occurring CBD. In considering DMH as a potential antiepileptic agent, its pharmacokinetics was studied in dogs (N = 8) after both iv (20 mg) and oral (80 mg) administration. After iv administration, DMH was rapidly distributed. DMH has a mean terminal half-life of 2 hr, its plasma levels decline in a biphasic fashion, and its total body clearance is 8.3 liters/hr. This clearance value, after being normalized to blood clearance by the use of mathematical equations, was less than one half of the value of the hepatic blood flow and its extraction ratio (E) by the liver is 0.39, DMH was observed to have a mean volume of distribution of 10 liters (or 0.5 liters/kg). In four of the eight dogs studied, DMH could not be detected in the plasma after oral administration. In the other four, the oral bioavailability was 3, 21, 39, and 43%, respectively. After oral administration, DMH has a low and variable bioavailability, due to a liver first-pass effect and incomplete absorption from the gastrointestinal tract. In comparison with CBD, DMH has a shorter half-life and lower clearance and volume of distribution values, and its liver extraction ratio is about one half that of CBD.