Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam.

Eight healthy male subjects received single 2-mg oral doses of lorazepam containing 24 muCi/mg of 2-14C-lorazepam. Multiple venous blood samples were drawn during the first 96 hr after the dose, and all urine and stool were collected for 120 hr after dosing. Concentrations of lorazepam and its metabolites in body fluids were determined by appropriate analytic techniques. Following a lag time, lorazepam was absorbed with an apparent first-order half-life of 15 min. The peak plasma concentration was 16.9 ng/ml, measured in the pooled sample drawn 2 hr after the dose, This corresponded to the time at which clinical effects appeared to be maximal. The apparent elimination half-life of lorazepam was about 12 hr. Biotransformation to a pharmacologically inactive glucuronide metabolite appeared to be the major mechanism of lorazepam clearance. A mean of 88% of administered radioactivity was recovered in urine, and 7% was recovered in stool. Lorazepam glucuronide comprised 86% of urinary reactivity; its renal clearance was 37 ml/min. Other identified metabolites included hydroxylorazepam, a quinazolinone derivative, and a quinazoline carboxylic acid; all of these were quantitatively minor.

Metabolism of equilin sulfate in the dog.

The metabolism of equilin sulfate was determined in female dogs receiving 2.5 mg/kg of [3H]equilin sulfate alone or in a preparation that contained all the components that are present in the conjugated equine estrogen product Premarin. The pharmacokinetic parameters of total radioactivity indicated that the drug is rapidly absorbed and it has a moderate half-life in plasma. The total radioactivity in plasma following administration of [3H]equilin sulfate as part of a mixture of conjugated equine estrogens had significantly lower peak concentration (Cmax), a lower area under the curve (AUC), a longer terminal half-life (t1/2) and a longer mean residence time (MRT) than when [3H]equilin sulfate was given alone, indicating that the other components in the conjugated equine estrogen preparation altered the pharmacokinetics of equilin sulfate. An average of 26.7 +/- 4.4% of the administered radioactive dose was excreted in urine of dogs receiving [3H]equilin sulfate. Again, a significantly lower percentage (21.4 +/- 6.3%, P = 0.023) was eliminated in urine of dogs receiving [3H]equilin sulfate in the conjugated equine estrogen preparation, indicating that the absorption of equilin sulfate was perhaps altered by the other components in the conjugated equine estrogen preparation. Metabolite profiles of plasma and urine were similar. Equilin, equilenin, 17 beta-dihydroequilenin, 17 beta-dihydroequilin, 17 alpha-dihydroequilenin and 17 alpha-dihydroequilin were present in both matrices. 17 beta-Dihydroequilin and equilin were the two major chromatographic peaks in plasma samples. 17 beta-Dihydroequilenin and 17 beta-dihydroequilin were the major metabolites in urine. In conclusion, following oral administration of [3H]equilin sulfate to dogs, the radioactivity is rapidly absorbed. The disposition of equilin sulfate is altered by the other components that are present in the conjugated equine estrogen preparation Premarin. The reduction of the 17-keto group and aromatization of ring-B are the major metabolic pathways of equilin in the dog.

Metabolic disposition of 14C-bromfenac in healthy male volunteers.

The metabolic disposition of 14C-bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50-mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 +/- 1.8 microg x equiv/mL, which was reached 1.0 +/- 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4-day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0- to 24-hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an alpha-keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.

Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite.

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

Dose-dependent pharmacokinetics of the antihypertensive 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5-(6H)-one in dogs and rats.

A sensitive and reproducible GLC assay was developed for determining 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one (I) in biological fluids, utilizing the electron-capturing capability of the heptafluorobutyryl derivative. After single 2.5- and 10-mg/kg oral and intravenous doses to three dogs, plasma concentration-time data for I were fitted to a biexponential equation and pharmacokinetic parameters were calculated. A dose-dependency for certain parameters, most notably total body clearance (ClT), was indicated. The difference in ClT for the low and high dose was statistically significant. After single 5-, 25-, and 50-mg/kg intragastric doses were given to rats, the decline in plasma concentrations of I with time followed a monoexponential equation. As with dogs, there was a disproportionate change in kinetic parameters with increasing dose for rats. While simple Michaelis-Menten kinetics were not evident, nonlinearity in biotransformation (intrinsic clearance) appeared to be the cause for the dose-dependent pharmacokinetics.

Determination of ciramadol in plasma by gas-liquid chromatography.

An analytical method for determining ciramadol concentrations in plasma was developed and evaluated for its specificity, precision, linearity, and sensitivity. GLC-electron capture detection of a dipentafluorobenzoyl derivative of the drug was used for quantitation. An isomer of the drug served as an internal standard. Resulting mean ratios of the peak height of derivatized drug to that of derivatized internal standard varied with a coefficient of variation that ranged from 3.8 to 11.1%. The mean ratio was linearly related to ciramadol content (8.75-175 ng) with a correlation coefficient greater than to 0.999. The minimum quantifiable concentration was 4 ng/ml with a 2-ml specimen. An application of this method is presented.

Disposition of (5H-dibenzo [a,d]cyclohepten-5-ylidene)acetic acid in laboratory animals.

The disposition of (5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (Wy-41,770), an anti-inflammatory agent, was investigated in rats, mice, rhesus monkeys, and dogs following single 12.5-mg/kg doses of 14C-labeled or unlabeled drug and in rodents receiving single 225-mg/kg doses of 14C-Wy-41,770. The drug was rapidly and well absorbed in all four animal species. Following an iv dose, plasma elimination half-lives of Wy-41,770 in monkeys and dogs were, respectively, 5.0 +/- 1.8 and 0.24 +/- 0.01 hr. Total body clearances (CL) of 1.8 +/- 0.2 ml/min/kg in monkeys and 7.7 +/- 1.1 ml/min/kg in dogs are low, indicating that, after an ig dose, little Wy-41,770 would be eliminated on first passage through the liver. The steady state volumes of distribution of 0.37 +/- 0.1 and 0.14 +/- 0.01 liters/kg, respectively, in monkeys and dogs are low, indicating limited extravascular distribution of Wy-41,770. Plasma half-lives of Wy-41,770 in rats and mice were, respectively, 10.8 and 8.4 hr. The longer half-life in rats compared to other animals is due to the extensive enterohepatic recycling of the drug in rats. The extensive cycling of the drug in rats may explain why ileocecal inflammation occurred in this species but not in mice and dogs following prolonged oral administration of high doses of Wy-41,770. Following a 12.5 mg/kg, ig dose, the rates of urinary excretion of radioactivity in monkeys, mice, and rats were, respectively, 73.4 +/- 10.7, 52.6 and 15.2% of the dose, whereas the fecal excretion was 9.1 +/- 3.7% in monkeys and 74.7% in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolic disposition of oxazepam in rats.

The metabolic fate of oxazepam in the rat is more complex than in larger animal species. Condensation of the diazepinyl ring and phase 1 transformations which lead presumedly via an epoxide to metabolites hydroxylated on the 5-phenyl moiety of oxazepam occurs in addition to glucuronidation, which has often been reported to be predominant in larger species. Unchanged oxazepam is the major compound in plasma, liver, and kidney, but phase 1 and phase ii metabolites also are found. In brain, though, only oxazepam is recognized, and a brain/plasma ratio of approximately 3-5:1 demonstrates that the drug has considerable affinity for that tissue. Excretion of oxazepam and its biotransformation products occurs mainly by the fecal route (70.7 +/- 6.0% of the dose) via biliary secretion. Glucuronides and sulfates of the hydroxylated metabolites and oxazepam and its glucuronide are secreted into bile, but only oxazepam, 4'-hydroxyoxazepam, and unknown polar metabolites constitute most of the fecal radioactivity, suggesting that enterohepatic circulation and intestinal metabolism are significant in the rat.

The metabolic disposition of dezocine in rhesus monkeys and female rats given 14C-dezocine intragastrically.

The metabolic disposition of 14C-dezocine has been investigated in male rhesus monkeys and female rats given intragastric 1- and 5- mg/kg doses, respectively. In both species the dose appeared to be rapidly and extensively absorbed. Concentrations of radioactivity were detected in monkey plasma 15 min after drug administration (the earliest sampling time) and reached a peak between 0.5 and 2 hr, whereas in the rat, high concentrations of radioactivity were detected in plasma and most tissues at 15 min. Biliary secretion was extensive in the monkey, but in the monkey as well as in the rat, the ultimate excretion of the radioactive dose was primarily through renal elimination. Tissue uptake of unconjugated drug was extensive in both species, and concentrations of drug in brain were substantially higher than those in plasma. Metabolism was mainly by glucuronidation in both species and also by sulfate formation in the female rat. Two minor imine metabolites produced by N-oxidation were indicated after a comparison with synthetic standards.

Metabolic disposition of ciramadol in rhesus monkeys and rats.

Studies on the metabolic disposition of ciramadol, a new orally effective analgesic, have been conducted in the rhesus monkey and male rat. The drug is well absorbed but undergoes extensive presystemic metabolism when given by the intragastric route (1 mg/kg) to rhesus monkeys. Maximum concentrations in plasma do not exceed 4 ng/ml. The major transformation occurs by glucuronidation and leads to two metabolites, and aryl O- and an alicyclic O-glucuronide. Phase I transformations are apparently minor and include N-demethylation, formation of benzoxazinyl metabolites from the reaction of endogenous acetaldehyde and formaldehyde with N-desmethylciramadol, and oxidation of the alicyclic and aromatic rings. Mass-spectrometric analyses of the isolated glucuronides and the minor phase I metabolites have been employed for structural assignments. Excretion of the intragastric dose occurs predominantly by the renal route. When given intramuscularly (1 mg/kg), concentrations of ciramadol peak at 1150 ng/ml by 0.5 hr after medication and decline rapidly to less than 7 ng/ml by 8 hr. Approximately 10% of the dose is excreted as unchanged ciramadol after im dosing. In male rats, the drug is absorbed rapidly after single 1-mg/kg intragastric doses and is taken up notably by liver, lung, kidney and spleen. Unlike its disposition in rhesus monkeys, ciramadol is present in plasma and excreted into urine mainly in the unconjugated form. Concentrations of drug in rat plasma are higher than those in rhesus monkey plasma, suggesting a smaller first-pass effect in the rat.

The disposition of [14C]iprindole in man, dog, miniature swine, rhesus monkey and rat.

1. Absorption of a single oral dose of [14C]iprindole was rapid in rats, rhesus monkeys, miniature swine, dogs and human volunteers. In all species except the rat, most of the radioactivity in the blood resided in the plasma. Small amounts of unchanged iprindole were detected in the plasma of rats and rhesus monkeys but not in man and miniature swine. 2. Radioactivity was excreted mainly in the urine of man, miniature swine and rhesus monkey, but in the faeces of rat and dog. 3. Urinary radioactivity was associated with basic (free and conjugated), acidic and highly polar, water soluble metabolites. At least 20 metabolites as well as small amounts of unchanged drug were detected in the basic fractions of each species' urine. 4. Many of these metabolites were common to all species; however, qualitative as well as quantitative differences were apparent. Mass-spectrometric analysis of several metabolites indicated N-demethylation and oxidation of the alicylic ring or a combination of both pathways.

Metabolic disposition of 14C-venlafaxine in mouse, rat, dog, rhesus monkey and man.

1. The metabolic disposition of venlafaxine has been studied in mouse, rat, dog, rhesus monkey and man after oral doses (22, 22, 2, and 10 mg/kg, and 50 mg, respectively) of 14C-venlafaxine as the hydrochloride. 2. In all species, over 85% of the administered radioactivity was recovered in the urine within 72 h, indicating extensive absorption from the GI tract and renal excretion. 3. Venlafaxine was extensively metabolized, with only 13.0, 1.8, 7.9, 0.3 and 4.7% dose appearing as parent compound in urine of mouse, rat, dog, monkey and man, respectively. The metabolite profile varied significantly among species, but primary metabolic reactions were demethylations and the conjugation of phase I metabolites. Hydroxylation of the cyclohexyl ring also occurred in mouse, rat and monkey, and a cyclic product was formed in rat and monkey. Glucuronidation was the primary conjugation reaction, although sulphate conjugates were also detected in mouse urine. 4. While no metabolite constituted more than 20% dose in any species except man, the major urinary metabolites were: mouse, N,O-didesmethyl-venlafaxine glucuronide; rat, cis-1,4-dihydroxy-venlafaxine; dog, O-desmethyl-venlafaxine glucuronide; monkey, N,N,O-tridesmethyl-venlafaxine; and man, O-desmethyl-venlafaxine.

Pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in laboratory animals.

1. The pharmacokinetics of venlafaxine have been evaluated in mouse, rat, dog and rhesus monkey after i.v. and/or i.g. doses of venlafaxine from 2 to 120 mg/kg either as single or repeated doses. 2. In rat, dog and monkey, venlafaxine is a high clearance compound with a large volume of distribution after i.v. administration. 3. Absolute bioavailability was low in rat and rhesus monkey (12.6 and 6.5%, respectively) and moderate in dog (59.8%). Other species differences were seen, including an elimination half-life of venlafaxine that was longer in dog and rhesus monkey (2-4 h) than in rodent (around 1 h). 4. In mouse, rat and dog, exposure to venlafaxine increased more than proportionally with dose, suggesting saturation of elimination. Exposure of venlafaxine decreased with repeated dosing in mouse and rat, but was unchanged in dog. 5. Exposure of animals to the bioactive metabolite, O-desmethylvenlafaxine (ODV), was less than that of venlafaxine itself. ODV was not detected in dog and not measurable in rhesus monkey receiving venlafaxine.

The metabolic disposition of 14C-ciramadol in humans.

Twelve subjects received single 15 mg oral doses of 14C-ciramadol. Excretion of the dose occurred almost entirely by the renal route (93.5 +/- 11.7 (S.D.)% of the dose), and only 0.7 +/- 0.6% of the dose was recovered in faeces indicating that absorption was essentially complete. More than 90% of the amount recovered in urine was excreted within 24 h after dosing. Unchanged drug accounted for 43.9 +/- 6.5% of the dose, while a phenolic glucuronide conjugate was the only major urinary metabolite accounting for a further 37.9 +/- 7.8%. A second glucuronide that was conjugated with the alicyclic ring was also identified but constituted only 2.3 +/- 0.6% of the dose. Concentrations of radioactivity in plasma reached a peak at 2 h after dosing and declined with a terminal disposition half life of 4.9 h. Only ciramadol and the aryl-O-glucuronide were detected in substantial amounts in plasma. Renal clearance of ciramadol amounted to 298 +/- 54 ml/min suggesting tubular secretion in addition to glomerular filtration.

The disposition of venlafaxine enantiomers in dogs, rats, and humans receiving venlafaxine.

A stereospecific high-performance liquid chromatographic (HPLC) method was developed for the quantitation of the enantiomers of venlafaxine, an antidepressant, in dog, rat, and human plasma. The procedure involves derivatization of venlafaxine with the chiral reagent, (+)-S-naproxen chloride, and a postderivatization procedure. The method was linear in the range of 50 to 5,000 ng of each enantiomer per ml of plasma. No interference by endogenous substances or known metabolites of venlafaxine occurred. Studies to characterize the disposition of the enantiomers of venlafaxine were conducted in dog, rat, and human, following oral administration of venlafaxine. The Cmax, area under the curve (AUC) and (S)/(R) concentration ratios of the (R)- and (S)-enantiomers were compared. In rats, the mean plasma ratio of (S)-venlafaxine to that of (R)-venlafaxine over 0.5 to 6.0 h varied from 2.97 to 8.50 with a mean value of 5.51 +/- 2.45. The Cmax, AUC0-infinity, and t 1/2 values of the (R)- and (S)-enantiomers in dogs were not significantly different from one another (P greater than 0.1). The mean ratios [(S)/(R)] of enantiomers of venlafaxine in human over a 2 to 6 h interval ranged from 1.33 to 1.35 with an overall ratio of 1.34 +/- 0.26 (n = 12). These ratios of the enantiomers [(S)/(R)] were not statistically different from unity (P greater than 0.1) indicating that the disposition of venlafaxine enantiomers in humans is not stereoselective and is more similar to that in dogs than that in rats.

Metabolic disposition of enciprazine, a non-benzodiazepine anxiolytic drug, in rat, dog and man.

1. The excretion and metabolism of enciprazine, an anxiolytic drug, was examined in rat, dog and man. 2. In rats and dogs that received 14C-enciprazine dihydrochloride orally and by i.v. injection, the drug was well absorbed. Radioactivity was excreted predominantly in the faeces of rats, equally in urine and faeces of dogs, and to a major extent in human urine. 3. Metabolic profiles, which were evaluated in urine and in rat bile, were similar following oral and i.v. dosing to rats and dogs. 4. Unchanged drug was not detected in rat, dog or human excreta. Glucuronide conjugates of 4-hydroxyenciprazine, m-desmethylenciprazine, p-desmethylenciprazine and enciprazine were detected in the excreta of all three species. A glycol metabolite was present only in rat bile and human urine. A metabolite desmethylated in the phenyl ring of the phenylpiperazine moiety also appeared to be present only in human urine. 5. Structural confirmation of the major metabolites in human urine and rat bile was accomplished by h.p.l.c.-mass spectrometry.

Determination of 17 alpha-dihydroequilenin in rat, rabbit and monkey plasma by high-performance liquid chromatography with fluorimetric detection.

A high-performance liquid chromatographic (HPLC) method with fluorescence detection for the determination of total (unconjugated and conjugated) 17 alpha-dihydroequilenin in male and female rat, female rabbit and male and female rhesus monkey plasma is described here. Plasma sample preparation involved hydrolysis with enzyme (Glusulase), addition of internal standard (14 beta-equilenin) and solvent extraction. The extracts were chromatographed on a C6, 5-microns reversed-phase HPLC column and detection was accomplished with a fluorescence detector operated at an excitation wavelength of 210 nm and an emission wavelength of 370 nm. The assay was linear over a range of 2.5 to 100 ng/ml in male and female rat plasma, and 5 to 500 ng/ml in female rabbit and male and female monkey plasma. The method was specific, accurate and reproducible (percent differences < 14.5; coefficients of variation < 9.5%) in all matrices examined. The applicability of this method was successfully tested by quantifying total plasma concentrations of 17 alpha-dihydroequilenin in ovariectomized female rats, ovariectomized female rabbits and a normal female rhesus monkey receiving 2.0, 8.3 and 0.1 mg/kg, respectively, of 17 alpha-dihydroequilenin sulfate intragastrically.