Oxazepam Glucuronide Research Articles

Oxidative versus conjugative biotransformation of temazepam

Twenty-four healthy volunteers, aged 21-59 years, received single 30 mg oral doses of the benzodiazepine hypnotic temazepam. Levels of intact temazepam were determined in multiple plasma samples drawn during 48 h after dosage. Intact temazepam, its direct glucuronide conjugate, and the conjugate of its demethylated (oxidized) metabolite oxazepam were measured in two consecutive 24-h urine collections. Mean kinetic variables for temazepam in plasma were: peak plasma level (Cmax), 873 ng ml-1; time of peak, 1.36 h after dosage; volume of distribution, 0.961 kg-1; elimination half-life 9.9 h; clearance, 1.16 ml min-1 kg-1. Volume of distribution increased significantly with body weight (r = 0.67, p less than 0.001), and Cmax decreased with weight (r = -0.58, p less than 0.01). Only 0.2 per cent of the dose was excreted as intact temazepam, and negligible amounts as intact oxazepam. However, 39 per cent of the dose was recovered as temazepam glucuronide, and oxazepam glucuronide accounted for another 4.7 per cent of the dose. The remainder was not accounted for. Thus, a significant fraction of temazepam clearance occurs by direct glucuronide conjugation, with the conjugate temazepam glucuronide excreted in urine. A much smaller fraction undergoes parallel oxidation to form oxazepam, which is subsequently conjugated to oxazepam glucuronide and excreted in urine.

Glucuronidation of oxazepam and paracetamol in severe hypothyroidism

Glucuronidation of oxazepam and paracetamol in severe hypothyroidism

Glucuronidation of Oxazepam Is Not Spared in Patients With Hepatic Encephalopathy

The disposition of oral oxazepam was investigated in seven patients with decompensated cirrhosis and encephalopathy and in nine healthy individuals to further examine the hypothesis of preservation of glucuronidation in liver disease. The patients showed a severe reduction in the quantitative liver function as assessed by estimation of the clearance of antipyrine; the median value was 9 ml.min-1 and the range was 6 to 12 ml.min-1. Apparent clearance of oxazepam in cirrhotic patients was 0.55 ml.min-1.kg-1, with a range of 0.46 to 1.24 ml.min-1.kg-1, compared with 1.19 ml.min-1.kg-1 and a range of 0.80 to 1.66 ml.min-1.kg-1 in the controls (p less than 0.05). The unbound clearance of oxazepam in patients was 4.1 ml.min-1.kg-1, with a range of 3.4 to 5.5 ml.min-1.kg-1, compared with 25.4 ml.min-1.kg-1, and a range of 16.7 to 43.7 ml.min-1.kg-1, p less than 0.001, in the controls. In patients with liver disease, the unbound clearance of oxazepam correlated significantly with antipyrine clearance (r = 0.88; p less than 0.05). The results suggest a reduced capacity for glucuronidation in patients with decompensated liver disease and severe hepatic failure that corresponds to the general reduction in the quantitative liver function.

The effect of dietary energy and protein deficiency on drug metabolism

The influence of a diet deficient in energy or protein on hepatic oxidation (Phase I reactions) and glucuronidation (Phase II reactions) in man has been examined. Nine healthy volunteers were fed an energy deficient diet (daily energy intake 4.3 MJ; daily protein intake 0.94 g/kg) and a protein deficient diet (daily energy intake 11.4 MJ; daily protein intake 0.31 g/kg) in random order. The control energy and protein intakes were 12.0 MJ and 1.52 g/kg, respectively. Each test diet period lasted 12 days. On Day 10, antipyrine 1000 mg and metronidazole 500 mg were given and elimination in saliva was determined. The metabolism of neither drugs was changed during the two dietary interventions, nor was their clearance to metabolites. On Day 12, the metabolism of oxazepam 15 mg was studied. The energy deficient and the protein deficient diet reduced the clearance rate of oxazepam by 20.3%, and 14.1% respectively. The elimination half-life was prolonged by 17.4% after the former and by 11.4% after the latter diet. Thus, both a low energy and a low protein intake decreased the glucuronidation of oxazepam, whereas no effect was observed on the rate of oxidation, expressed as the metabolism of antipyrine and metronidazole.

Clinical pharmacokinetics and endocrine disorders. Therapeutic implications.

Endocrine disorders are common and produce widespread changes in cellular and organ function. Alterations in the sensitivity of patients with thyroid disorders to digoxin, anticoagulants and sedatives have been recognised for many years. Many of the recently documented kinetic alterations in endocrine patients are explicable on the basis of disease-induced changes in hepatic drug metabolism, protein binding and renal function. In hyperthyroidism the rate of absorption of paracetamol, propranolol and oxazepam is increased due to increased gastrointestinal motility. The volume of distribution of propranolol and digoxin is increased and there is decreased binding of both basic and acidic drugs as a consequence of alterations in alpha 1-acid glycoprotein and albumin concentration. The rate of glucuronidation of paracetamol and oxazepam is increased in hyperthyroidism. While oxidative metabolism of antipyrine, propranolol, metoprolol and theophylline is enhanced, the clearance of a number of other agents, including diazepam, warfarin, antithyroid drugs and phenytoin, is unaltered. The systemic clearance of propranolol is enhanced as a consequence of a 50% increase in liver blood flow. The rate of elimination of a number of endogenous substances, including cortisol, thyroid hormones and insulin, also appear to be enhanced. Hyperthyroidism has a variable effect on renal function, with a possible increase in digoxin elimination, but no effect on the clearance of renally excreted beta-blockers, atenolol, sotalol and nadolol. These kinetic changes suggest that individualization and higher than normal dosage of propranolol is necessary to control hyperthyroidism, and in thyrotoxic atrial fibrillation higher doses of digoxin or additional therapy with beta-blockers, or verapamil, may be indicated. The increased sensitivity of thyrotoxic patients to warfarin suggest care with dosage and frequent monitoring of response are warranted. Less information is available concerning hypothyroidism, but there is a general trend for decreased absorption of paracetamol and propranolol. In addition, the volume of distribution of digoxin is reduced, as is renal clearance. Limited studies suggest no alteration in the glucuronidation of oxazepam, but antipyrine clearance appears to be reduced. Steady-state propranolol concentrations are elevated in hypothyroidism and there appears to be a decreased metabolism of thyroid hormones and cortisol. Preliminary information suggests the binding of propranolol is increased. Thus, in the treatment of hypothyroid patients, a lower dosage of propranolol may be required.(ABSTRACT TRUNCATED AT 400 WORDS)

The influence of diflunisal on the pharmacokinetics of oxazepam.

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/- 18 ng ml-1 (mean +/- s.e. mean) to 241 +/- 10 ng ml-1 and total area under the plasma concentration-time curve (AUC) significantly decreased from 5536 +/- 819 ng ml-1 h to 4643 +/- 562 ng ml-1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/- 227 ng ml-1 h to 8116 +/- 644 ng ml-1 h and its elimination half-life increased from 10.0 +/- 0.6 h to 13.0 +/- 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/- 2 ml min-1 to 46 +/- 3 ml min-1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml-1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/- 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.

Inhibition of diazepam metabolism in microsomal- and perfused liver preparations of the rat by desmethyldiazepam, N-methyloxazepam and oxazepam.

Hydroxylated metabolites of diazepam can be conjugated and are therefore generally thought not to affect the metabolism of diazepam. Liver microsomes, obtained from phenobarbital-pretreated rats, showed an inhibition of diazepam (10(-5) M) metabolism by desmethyldiazepam as well as by N-methyloxazepam or oxazepam (5 X 10(-5) M). In a single-pass perfusion of the rat liver an inhibition of diazepam disposition by exogenously administered desmethyldiazepam and by hydroxylated diazepam metabolites was also demonstrated. No oxazepam glucuronides were found after oxazepam infusion. However, infusion with N-methyloxazepam resulted in large amounts of oxazepam-glucuronides. The results indicate that administration of N-demethylated as well as hydroxylated metabolites may result in inhibition of the metabolism of their precursor. If hydroxylated metabolites are formed in situ they become more easily conjugated in comparison with administered hydroxylated metabolites and are therefore less effective as inhibitor.

Effect of brussels sprouts and cabbage on drug conjugation.

Ten healthy subjects were fed three diets for 10 days each: a control diet, a cabbage and brussels sprouts--containing diet, and the control diet a second time. Oxazepam was taken on day 7 and acetaminophen on day 10 of each dietary regimen. The test diet stimulated the metabolism of acetaminophen, at least in part by enhanced glucuronidation, as evidenced by a 16% decrease in mean plasma AUC, a 17% increase in mean metabolic clearance rate, an increased ratio of acetaminophen glucuronide to acetaminophen in plasma from 1 to 11 hr after drug and an 8% increase in mean 24-hr urinary recovery of acetaminophen glucuronide, which returned toward control when the subjects were fed the control diet a second time. There were no comparable changes in the metabolism of acetaminophen to acetaminophen sulfate. When the subjects ate the test diet, 24-hr urinary recovery of the cysteine conjugate and of 3-methoxyacetaminophen sulfate, end-products of minor oxidative pathways, the former involving a toxic intermediate, decreased 13% and 22%. Cabbage and brussels sprouts induced a 17% decrease in mean plasma AUC and a 19% increase in mean metabolic clearance rate for oxazepam, but there was no change in mean plasma t1/2 for this drug, nor was there a change in ratio in plasma of oxazepam glucuronide to oxazepam.

Multiple-dose kinetics and dialyzability of oxazepam in renal insufficiency.

7 patients with chronic renal insufficiency (4 of whom were on maintenance hemodialysis) and 6 healthy controls received single 15-mg oral doses of oxazepam for 7 consecutive days. Multiple venous blood samples drawn during the 72 h after the final dose were analyzed for concentrations of oxazepam and its glucuronide metabolite, and the extent of oxazepam protein binding. In hemodialysis patients, the final dose was taken just prior to dialysis; arterial (inflow) and venous (outflow) plasma was analyzed as well as dialysate. Mean steady-state plasma concentrations (Css) of total (free and bound) oxazepam in nondialysis renal failure patients (133 ng/ml) were lower, and clearance of total oxazepam (2.5 ml/min/kg) higher, than the corresponding values in controls (330 ng/ml and 1.2 ml/min/kg, respectively). However, these differences were attributable to the greatly increased oxazepam free fraction in renal insufficiency patients (12.0 vs. 4.5% unbound). After correction for individual values of free fraction, Css and clearance of pharmacologically active, unbound oxazepam were essentially identical between groups (14.6 vs. 14.4 ng/ml; 27 vs. 28 ml/min/kg). Compared to controls, Css of the inactive glucuronide metabolite of oxazepam among renal failure patients was greatly increased (2,377 vs. 372 ng/ml) and clearance greatly reduced (0.16 vs. 0.89 ml/min/kg) since excretion of the glucuronide depends on glomerular filtration. Dialyzability of oxazepam and oxazepam glucuronide was minimal. Arterial and venous plasma concentrations were essentially identical, and dialysate concentrations were a small fraction of those in plasma. Thus renal insufficiency does not alter the clearance or Css of pharmacologically active, unbound oxazepam.

Effect of pentobarbital on the formation of diastereomeric oxazepam glucuronides in man: analysis by high performance liquid chromatography.

Barbiturate treatment can enhance drug oxidation in man, but its effects on glucuronidation of clinically used drugs are unknown. We have studied the effect of 10 days treatment with pentobarbital on oxazepam glucuronidation in six volunteers. The diastereomeric (+ and -) glucuronides in urine were analyzed separately by high performance liquid chromatography and oxazepam in plasma by gas liquid chromatography. The area under the plasma concentration time curve for oxazepam (15 mg sod) decreased after pentobarbital treatment in all subjects, mean 10.4 before and 6.9 h X mumol/l after treatment (P less than 0.05) and oxazepam's plasma clearance increased by about 50 per cent. The glucuronides appeared more rapidly in the initial urinary fractions. The ratio between the glucuronides (+/-) appearing in urine decreased on pentobarbital treatment. Our data indicate that pentobarbital treatment increases the clearance of oxazepam by increased glucuronide conjugation, probably reflecting barbiturate induced changes of UDP glucuronyltransferase.

Cimetidine spares the glucuronidation of lorazepam and oxazepam

Lorazepam (Ativan) disposition and elimination were studied in 8 normal subjects before and after 1 wk of cimetidine therapy, 300 mg taken orally four times a day. In 4 of these 8 normal subjects the disposition and elimination of oxazepam (Serax) were also studied before and after similar treatment with cimetidine. Cimetidine did not alter the elimination of either lorazepam or oxazepam. Since both drugs are eliminated exclusively after conjugation as glucuronide, this study demonstrates a relative sparing of this pathway of biotransformation of drugs in subjects receiving cimetidine.

Mass screening and confirmation of diazepam in urine by EMIT-thin-layer chromatography.

A rapid, sensitive, and specific procedure is described for the mass screening and confirmation of diazepam (Valium) in urine at levels as low as 0.5 micrograms/mL. Raw urine specimens are screened directly by the enzyme multiplied immunoassay technique, and those screened positive are confirmed by thin-layer chromatography. Diazepam and its metabolites are converted to benzophenones; diazepam, 3-hydroxydiazepam, and its glucuronide yield 2-methylamino-5-chlorobenzophenone (MACB); whereas N-desmethyldiazepam, oxazepam, and oxazepam glucuronide yield 2-amino-5-chlorobenzophenone (ACB). The two benzophenones are well separated by a solvent system of petroleum ether:glacial acetic acid (90:10) and can be detected under ultraviolet light. A specimen reported positive for diazepam must produce spots for both ACB and MACB. No other benzodiazepines used in the United States or other urinary substances have been found to interfere; thus the procedure described is specific for for diazepam.

Gas chromatographic-mass spectrometric determination of intact C 3-hydroxylated benzodiazepine glucuronides in urine

A method is described for the determination of C 3-hydroxylated benzodiazepine glucuronides in biological samples. Oxazepam and lorazepam glucuronides are measured as methyl esters and trimethylsilyl derivatives by a gas chromatographic procedure. The applicability of the method has been tested on the urine of rats, guinea pigs, rabbits and man, receiving oxazepam orally. Oxazepam glucuronide was not found in rat urine but it was present in the urine of rabbits (5.7% of the administered dose), guinea pigs (9.5 %) and man (13.4–26.9%).

Identification of oxaxepam and lorazepam glucuronides by chemical ionization mass spectrometry.

Die Glucuronide des Oxazepams und Lorazepams wurden aus dem Harn von Zwergschweinen, denen die entsprechenden Benzodiazepine verabreicht wurden, isoliert. Die Metaboliten wurden durch Analyse der Spaltprodukte gekennzeichnet. Massenspektrometrie der Trimethylsilylderavite war fur die Struktur derO-Glucuronide beweisend.

Prazepam metabolism after chronic administration to humans.

Abstract1. 14C-Prazepam (10 mg) was administered to a group of men before and after a course of treatment (10 mg, t.i.d. for one week) with non-radioactive prazepam.2. Evaluation of the urine collected for seven days after each 14C-prazepam treatment showed that the multiple dosing did not affect (a) the urinary excretion kinetics of total 14C, (b) the relative proportions of prazepam metabolites excreted non-conjugated or as glucuronide and sulphate conjugates or (c) the quantities of desalkylprazepam, 3-hydroxyprazepam glucuronide and oxazepam glucuronide excreted in the urine.3. The major metabolic pathway (prazepam→-3-hydroxyprazepam→oxazepam) proceeded much faster with the 10 mg dose used in this study than it did in an earlier study involving the administration of 25 mg of prazepam.

Prazepam metabolism by man.

The absorption, excretion, and biotransformation of 14C‐labeled prazepam were studied in man. Slow, sustained absorption followed the administration of a single oral dose. The peak level of the blood radioactivity was observed after 6 hours. Clearance from the blood was also slow, particularly with respect to the unconjugated forms of the drug. Unlike diazepam, the major phase 1 reaction for prazepam was hydroxylation at carbon‐3 rather than dealkylation. Initially, the principal urinary metabolite was 3‐hydroxyprazepam glucuronide. Oxazepam glucuronide was excreted in increasing quantities over the 48 hour study period so that its total excretion approached that of 3 ‐hydroxyprazepam glucuronide. No unaltered prazepam was detected in the urine and the level of desalkylprazepam was low. Several unidentified radioactive glucuronides and sulfates were also excreted in the urine.

Prazepam Metabolites in Dog Urine

Within 24 hr. after receiving a single oral dose (10 mg./kg.) of 14C-labeled prazepam, two dogs excreted small quantities (4.6 and 1.8%) of the radioactivity into the urine. Thin-layer chromatograms showed the presence of at least eight radioactive compounds in these urine collections. Six of the labeled compounds were identified, and accounted for 86% of the 14C in the urine from Dog 1 and 95% of the 14C in the urine from Dog 2. These compounds and their contributions to the urinary radioactivity were: prazepam (1%, Dog 1; 0.2%, Dog 2); desalkylprazepam (2%, Dog 1; 0.4%, Dog 2); 3-hydroxyprazepam glucuronide (9%, Dog 1; 11%, Dog 2); oxazepam (14%, Dog 1; 3%, Dog 2); oxazepam glucuronide (52%, Dog 1; 72%, Dog 2), and 4′-hydroxyoxazepam glucuronide (8%, Dogs 1 and 2).

Prazepam Metabolism by Dogs

Prazepam-5-14C [7-chloro-l-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one] was primarily eliminated with the feces in unaltered form following the oral administration of 10 mg./kg. to dogs. Prazepam resembled diazepam and oxazepam in the low blood levels and extensive fecal excretion. Further similarity of prazepam to diazepam was shown by the biotransformations involving dealkylation and hydroxylation. The major urinary metabolite from prazepam is oxazepam glucuronide. The possible presence of unchanged prazepam and/or 3-hydroxyprazepam glucuronide as well as 4′-hydroxy oxazepam glucuronide in the urinary excretion is also indicated.

Metabolism of diazepam in dogs: Transformation to oxazepam

On administration to dogs, diazepam is demethylated at the 1-nitrogen and through a novel metabolic pathway is hydroxylated at the 3-carbon of the seven-membered ring. The unhydroxylated demethylation product is excreted in the free form and the 3-hydroxy derivatives are excreted as the glucuronides. No unchanged drug can be detected in the urine. The major metabolite is oxazepam glucuronide.