The effect of extreme old age on the pharmacokinetics and pharmacodynamics of orally administered oxazepam 15 mg was studied in 10 healthy elderly (age 80-94 years) institutionalised subjects and 10 healthy young controls (age 26-42 years). The total oxazepam clearance was 1.24 (0.91-1.80) ml min-1 kg-1 (median and range) and 1.44 (0.88-2.13) ml min-1 kg-1 in the elderly and young, respectively (NS), and the elimination half-lives were 8.1 (5.5-10.8) h and 5.7 (4.9-6.2) h. respectively (P less than 0.01). The percent of unbound oxazepam was greater in the elderly; 9.8 (8.1-13.3)% as opposed to 5.1 (3.7-5.9)% in the young (P less than 0.0001). Clearance of unbound oxazepam was lower in the elderly, median values being 13.8 (7.1-21.1) ml min-1 kg-1 compared with 30.3 (18.3-41.5) ml min-1 kg-1 in the young (P less than 0.0001). A single 15 mg dose oxazepam decreased the ability of the elderly to perform a finger tapping test at 3 h but not 8 h after drug administration, whereas placebo had no effect at either times. No effect was observed in the young subjects.

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.

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 +/- 6 years and 8 aged 30 +/- 6 years. 2 The plasma clearance of metronidazole was 1.20 +/- 0.53 and 1.25 +/- 0.22 ml min-1 kg-1, the volume of distribution 0.77 +/- 0.27 and 0.77 +/- 0.09 1 kg-1 and the half-life 7.8 +/- 1.9 and 7.2 +/- 0.9 h in elderly and young subjects, respectively (P less than 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 +/- 14 and 21 +/- 3 mM min-1 (P less than 0.05) whereas its half-life was 21 +/- 14 and 12 +/- 2 h (P less than 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 +/- 21% and 87 +/- 6% of dose in elderly and young subjects, respectively (P less than 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

1. The oral kinetics of oxazepam after a single 15 mg oral dose was investigated in six healthy volunteers before and during concomitant administration of the beta-adrenoceptor antagonists propranolol (80 mg) and labetalol (200 mg) (racemates). 2. A possible pharmacodynamic interaction between oxazepam and the beta-adrenoceptor antagonists was examined using a simple reaction time test (SRT) and by measurement of postural sway. 3. The kinetics of oxazepam were not affected significantly by propranolol or labetalol, although oxazepam and labetalol share the glucuronidation pathway. 4. The SRT was increased by combination of both beta-adrenoceptor antagonists with oxazepam, with the greatest increase after the coadministration of oxazepam with propranolol. Administration of the beta-adrenoceptor antagonists alone had no significant effect. 5. Postural sway was affected significantly only by the combination of oxazepam and propranolol.

1. The effect of severe hypothyroidism on the pharmacokinetics and pharmacodynamics of oxazepam 15 mg given orally (n = 10) and the metabolism of paracetamol 750 mg given intravenously (n = 8) was investigated before and after treatment with levothyroxine. 2. The median total and unbound clearance of oxazepam increased significantly during the study period from 0.78 ml min-1 kg-1 (0.40-1.25) to 1.22 ml min-1 kg-1 (0.66-1.94) and from 9.3 ml min-1 kg-1 (5.2-14.2) to 15.9 ml min-1 kg-1 (7.8-21.8), respectively (P less than 0.01). 3. The elimination half-life of oxazepam was prolonged by hypothyroidism to a median (range) value of 9.3 h (5.4-21.9) compared with 7.5 h (4.8-10.5) in the euthyroid state (P less than 0.05). 4. Hypothyroidism did not affect the protein binding of oxazepam; median values of the free percentage being 8.2% as compared with 7.7% when euthyroid. 5. The median (range) clearance of paracetamol under hypothyroid conditions was 3.12 ml min-1 kg-1 (1.64-4.40) and 4.70 ml min-1 kg-1 (3.18-5.70) following replacement therapy (P less than 0.01). This increase was associated with a comparable increase in the partial clearance to the glucuronide metabolite: 1.86 ml min-1 kg-1 to 2.70 ml min-1 kg-1. 6. Hypothyroidism was associated with decreased performance in a finger tapping test that was exacerbated by oxazepam. When the patients were euthyroid oxazepam did not produce any effect.

Fifteen otherwise healthy asthmatics with reversible airway obstruction were treated with salbutamol (8 mg slow release twice daily) and theophylline (300 mg twice daily). Each drug was administered for 4 weeks in a double-blind randomized crossover trial. Irrespective of which drug was given first, salbutamol increased antipyrine clearance significantly by a factor of 1.10 and 1.15 after 2 and 4 weeks of treatment, respectively. Theophylline did not change antipyrine clearance. There was no correlation between the extent of change in antipyrine clearance during either of the drug treatments and alterations in lung function as assessed by changes in peak flow, forced vital capacity and forced expiratory volume in first second.

A very low calorie diet (Prodi) was administered to eleven otherwise healthy obese subjects for fourteen days. The daily intake of protein was 52.7 g and carbohydrate 25.7 g, corresponding to 360 kcal. The clearance of oxazepam and antipyrine was investigated before and after the diet period.

The influence of rifampicin (450 mg/day for 28 days) on the hepatic microsomal enzymes and thyroid function variables were investigated in 13 healthy male volunteers. After 14 and 28 days of treatment a significant increase in median thyroid volume (determined ultrasonically) was demonstrated (20 ml, range 13-28 before; 26 ml, range 18-48 at day 14, and 24 ml, range 17-40 at day 28) (p less than 0.01). A significant decrease in median serum free T4 index levels was seen (94.1 arbitrary units, range 80.1-123.4 before treatment; 86.8, range 71.7-102.0 at day 14, and 85.3, range 65.5-131.3 at day 28) (p less than 0.01). Serum T4, T3, T3 resin uptake, free T3 index and TSH levels were not significantly altered. Hepatic microsomal enzyme activity assessed by antipyrine clearance was significantly increased (approximately by 85%) at day 14 and 28, whereafter it normalized. The study supports the hypothesis that the increase in thyroid volume after treatment with rifampicin and other hepatic enzyme system inducers (e.g. phenytoin and carbamazepine) is a compensatory mechanism caused by an increased hepatic degradation of thyroid hormones.

1. Antipyrine clearance and average daily consumption of tobacco, alcohol and coffee/tea were determined in 303 healthy men. 2. The antipyrine clearance was positively correlated with the consumption of tobacco (r = 0.24; P less than 0.0001) and coffee/tea (r = 0.18; P less than 0.001), and negatively with age (r = -0.14; P less than 0.05) and the alcohol consumption (r = -0.13; P less than 0.05). 3. The multiple regression coefficients suggested an increase in antipyrine clearance of 0.8% per daily cigarette or cup of tea and 1.4% per daily cup of coffee; the decrease per daily drink or year of age was 2.8% or 0.4%, respectively.

After 96 administrations of metronidazole to 36 subjects, it was found that the clearance could be determined from one plasma sample, the dose, and a volume of distribution estimated from sex, age, body weight, and height, without loss of precision and accuracy compared with conventional clearance determinations (r greater than 0.97). In 230 sample pairs the plasma and saliva concentrations of metronidazole were identical (r = 0.99). In 119 subjects the one-sample clearance of metronidazole was unimodally distributed. Body weight (r = 0.28) and the alcohol consumption (r = 0.23) correlated with the metronidazole clearance. In the same subjects the consumption of tobacco (r = 0.28), alcohol (r = -0.19), coffee/tea (r = 0.27), age (r = -0.24), and sex (r = 0.28) correlated with the antipyrine clearance. The clearances of metronidazole and antipyrine were correlated (r = 0.34). The differential influence of the environmental factors on the elimination rates supports differential metabolism of metronidazole and antipyrine.

Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t1/2β) 6.7 h, total clearance (CL) 1.07 ml·min−1·kg−1, volume of distribution (Vc) 0.27 l·kg−1 (0.21–0.49) and volume of distribution at steady-state (Vss) 0.59 l·kg−1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min−1·kg−1 and a distribution volume of 12.3 l·kg−1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t1/2β at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CLR) of the glucuronide metabolite was 1.10 ml·min−1·kg−1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.

In nine healthy volunteers, the clearance and metabolism of acetaminophen 1000 mg i.v. was evaluated with and without two concomitant oral doses of codeine in order to investigate a possible interaction. Plasma acetaminophen was followed for 720 min and urine was collected for 24 h after each dose for determination of metabolites.

The time course of the effect of cimetidine on the pharmacokinetics of metronidazole was investigated in 6 healthy volunteers.

Cimetidine 1000 mg/day and phenobarbital 100 mg/day were given to five healthy volunteers for 13 days in order to investigate the combined effect and time course of inhibition and induction on hepatic drug metabolism. The one-sample antipyrine saliva clearance (APC) and urinary metabolite profile were measured weekly, once before, two times during and four times after drug administration. On the second day of drug treatment APC was 0.7 fold and the formation clearance of the 3 oxidized metabolites 0.6 fold decreased owing to an early inhibition by cimetidine (p less than 0.05). After 8 days of concomitant drug administration, i.e. when the drug mediated inhibition and induction are supposed to be at maximum, mean APC was 0.85 times the initial value (p greater than 0.05), whereas the formation clearances of nor- and 3-hydroxymethylantipyrine were still significantly depressed. Four and 11 days after drug withdrawal, when phenobarbital, but not cimetidine could be demonstrated in plasma, APC was 1.2 times the initial value (p less than 0.05). The results suggest, that the respective effects of cimetidine and phenobarbital on antipyrine elimination are additive, when given concomitantly, but that cimetidine exerts a relatively greater inhibition in the phenobarbital induced state.

Sex-related differences were prospectively studied in patients with the first presentation of alcoholic liver disease. Among 42 patients the diagnosis was cirrhosis in 8 women and 15 men, alcoholic hepatitis in 4 women and 1 man, steatosis in 6 women and 6 men, and no histologic changes were found in the liver biopsy specimens from 2 men (p greater than 0.1). The median (range) antipyrine clearance was 14.6 (1.0-64) versus 17.2 (3.0-83) ml/min and the clinical score in accordance with the Pugh modification of the Child-Turcotte classification was 8 (5-13) versus 8 (5-11) in the women and men, respectively (p greater than 0.05). In 5 women and only 1 man the antipyrine clearance was less than 5 ml/min, indicating an almost total loss of functional liver mass (p less than 0.05), whereas the Pugh score was above 11 in 6 women, but not in any of the men (p less than 0.05). On an average, the men estimated their total lifetime consumption of alcohol to be 2.1 times greater and the number of days they had consumed more than 5 drinks 2.9 times higher than the women (p less than 0.05). These ratios are reduced to 1.4 and 1.7, respectively (p greater than 0.05), if the female alcohol intake is adjusted to the average male volume of distribution. The results support the concept that women may develop similar, and sometimes even more severe, liver disease after consumption of less alcohol than men. The apparent difference in susceptibility to alcohol may be partly explained by differences in volume of distribution.

The influence of prednisolone on the elimination of antipyrine has been investigated. The one-sample antipyrine clearance was estimated in 23 outpatients with obstructive lung disease before and after treatment with prednisolone 30 or 50 mg/day for 7 days.