Critical factors for pharmacokinetics of zopiclone in the elderly and in patients with liver and renal insufficiency.

Zopiclone, a new hypnotic cyclopyrrolone, undergoes extensive hepatic metabolism. The carrier of hypnotic activity is the parent compound; however, knowledge of its metabolic profile is essential for the understanding of pharmacokinetic changes in various pathophysiological conditions. In 45 healthy young volunteers, zopiclone had a Tmax of 0.5. A first-pass effect of 20% resulted in an absolute bioavailability, F, of 77%. The volume of distribution ratio Vdc/Vdt was 3.2. The plasma half-life (t1/2) was 5.1 h. A metabolic ratio of 3.7 and 4.6 was found for the two main urinary metabolites, N-oxide and N-desmethyl derivatives. No modifications of kinetics were seen after chronic treatment. In eight patients with liver insufficiency, the main changes (delayed Tmax, 3.5 h, higher plasma concentrations with an increased F of 97%, prolonged t1/2 of 8.4 h) were essentially due to a reduced hepatic metabolic clearance, as shown by a decreased metabolic ratio for the two main metabolites. In 18 patients with renal insufficiency, the only major modification was an increased bioavailability (F of 115%) probably due to a relative decrease of the Vdc. In 19 elderly subjects, the main findings were a decreased metabolic clearance, as shown by decreased metabolic ratios, and an inversion of the Vdc/Vdt ratio, evoking the changes seen in renal insufficiency. The increase in F (168%) and the age-dependent increase in plasma t1/2 (8.1 h) in the oldest subjects (over 74 years of age) can be explained by this double mechanism. On the basis of these findings, a reduction of the initial zopiclone dose from 7.5 to 3.5 mg/day is recommended for patients with severe liver insufficiency and patients over 70 years of age with liver insufficiency.

A repeated dose pharmacokinetic study of a new hypnotic agent, zopiclone (Imovane).

Eleven volunteers were dosed once daily for 14 days with zopiclone (7.5 mg/day). The peak plasma zopiclone concentration (65 ng/ml) occurred at 1.4 h after dosing and thereafter declined by a biexponential process, with half-lives of 2.0 and 6.5 h, to 3 ng/ml by 24 h after dosing. Repeated once daily dosing did not markedly alter the peak plasma zopiclone concentration or the pharmacokinetic parameters of absorption or elimination.

Pharmacokinetics of metronidazole in patients with varying degrees of renal failure.

Twenty-nine patients with varying degrees of renal insufficiency were given a single intravenous dose of metronidazole (500 mg). Plasma and urinary concentrations of metronidazole and two major metabolites were determined using a specific high performance liquid chromatographic assay. The pharmacokinetic parameters of metronidazole elimination half-life, area under the metronidazole concentration against time curve, apparent volume of distribution, metronidazole clearance and predicted degree of accumulation of metronidazole on repeated dosing were not statistically significantly affected by renal inadequacy of any degree. The urinary excretion of metronidazole in patients with moderate or severe renal insufficiency was approximately half the value in healthy volunteers. The renal clearance of metronidazole was significantly greater in healthy volunteers compared to renally insufficient patients, but accounted for less than 10% of the total metronidazole clearance in all groups. The elimination half-life and predicted accumulation (on three times daily dosing) of metabolite I [1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole] were significantly increased with decreasing renal function from 9.2 h and 2.3, respectively, in healthy volunteers to 34 h and 6.7, respectively, in patients with total renal failure. The degree of accumulation of this metabolite on repeated dosing is probably of limited clinical significance in all patients except those with severe or total renal failure for reasons detailed in the text. The elimination half-life and predicted accumulation on three times daily dosing of metabolite II, [2-methyl-5-nitroimidazole-1-acetic acid] increased rapidly with decreasing renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary pharmacokinetics of orally administered ketoprofen in man.

The urinary pharmacokinetics of ketoprofen were compared after administration of single doses of standard ketoprofen capsules or two sustained-release pellet formulations of ketoprofen to nine healthy volunteers, using a specific and sensitive high-performance liquid chromatographic assay procedure. The sustained-release pellet formulation with the faster in vitro release characteristics was shown to be bioequivalent to ketoprofen capsules ('Orudis'). The mean (+/- standard deviation) apparent elimination half-life of ketoprofen after this sustained-release formulation was 7.4 +/- 3.1 h, compared with 4.1 +/- 0.85 h after ketoprofen capsules. The sustained-release formulation with the slower in vitro dissolution characteristics also exhibited slower in vivo dissolution, but was only 65% bioavailable, compared to ketoprofen capsules. A disproportionately large degree of elimination of free ketoprofen was observed between 0-6 h after dosing with ketoprofen capsules. This result could be explained by a saturable mechanism in the metabolism of ketoprofen to its glucuronide. however, since the renal excretion of free ketoprofen is not a major route of ketoprofen elimination, relatively large alterations in this parameter will not markedly alter elimination half-life or area under the plasma ketoprofen concentration against time curve. Thus, the clinical significance of such a mechanism is probably negligable.

Comparative pharmacokinetics of ketoprofen derived from single oral doses of ketoprofen capsules or a novel sustained-release pellet formulation.

Nine healthy male volunteers took part in a crossover study to compare the pharmacokinetics of ketoprofen after administration of a single oral dose (200 mg) of ketoprofen as 'Orudis' capsules or encapsulated sustained-release pellets, 'Oruvail'. The mean +/- standard deviation values for highest observed plasma ketoprofen concentrations were determined by high performance liquid chromatography to be 23 +/- 11 micrograms ml-1 at 0.82 +/- 0.18 h after dosing with ketoprofen capsules and 3.5 +/- 1.0 micrograms ml-1 at 4.9 +/- 1.0 h after dosing with sustained-release pellets. The apparent ketoprofen elimination half-lives after these treatments were 3.3 +/- 1.2 h and 8.4 +/- 3.4 h, respectively. The systemic availability of ketoprofen was essentially the same after each treatment. Administration of sustained-release pellets (containing 200 mg ketoprofen) once every 24 h is predicted to produce similar average and markedly higher minimum plasma ketoprofen concentrations than are produced by ketoprofen capsules (100 mg) every 12 h, and similar minimum plasma ketoprofen concentrations to those achieved by dosing ketoprofen capsules (50 mg) every 6 h. Once-daily administration of a non-steroidal anti-inflammatory agent has an obvious therapeutic advantage over more frequent dosing. This study suggests that the sustained-release pellet formulation described herein is a suitable formulation for once-daily administration of ketoprofen.

A pharmacokinetic study of repeated doses of a new controlled release form of ketoprofen.

Nine volunteers were dosed once daily for 15 days with a controlled release formulation of ketoprofen. The peak plasma ketoprofen concentration (4.2 micrograms/ml) and apparent elimination half-life (8.4 h) did not markedly alter during the course of the study. Plasma ketoprofen concentrations at 24 h after dosing were 0.79 micrograms/ml. These minimum ketoprofen concentrations suggest that this formulation is suitable as a once daily dosing regimen.

Observations on the clinical pharmacology and plasma concentrations of diacetolol, the major human metabolite of acebutolol.

1 The pharmacological effects and plasma levels of diacetolol, the major human metabolite of acebutolol, were measured in a double-blind, balanced study in which five healthy men received single oral doses of diacetolol 100, 200, 400 and 800 mg, or placebo, at weekly intervals. 2 Resting and exercise heart rate (HR), forced expiratory volume in 1 second (FEV1), resting and exercise peak expiratory flow rate (PEFR), and plasma concentrations of diacetolol were determined at 0, 2, 4, 6, 8 and 24 h after each treatment. 3 Diacetolol caused a slight dose-related reduction in resting HR and a substantial dose-related reduction in exercise HR. AT the same time it was found that diacetolol had no significant effects on FEV1 and resting and exercise PEFR. 4 Mean highest observed plasma concentrations (ng/ml) of diacetolol were 177 at a mean of 4.4 h after the 100 mg dose, 243 at 4.0 h after the 200 mg dose, 807 at 5.2 h after the 400 mg dose, and 1,306 at 4.4 h after the 800 mg dose. 5 Using the mean data, there was a strong correlation (r = 0.90) between % reduction in exercise HR and the logarithm of the plasma concentration of diacetolol. 6 Diacetolol exhibits marked cardiac beta-adrenoceptor blocking activity in man which is still evident 24 h after the administration of the higher doses of the drug. No adverse effects on pulmonary function could be detected.

Removal of metronidazole by haemodialysis.

The removal of the anti-anaerobic antibiotic metronidazole has been studied in oliguric patients. The drug and its principal metabolite are rapidly removed by haemodialysis so that the plasma concentration quickly falls below the therapeutic range. Hence a further dose of metronidazole would be needed after dialysis to restore an adequate plasma concentration.

Brain concentrations of phenytoin, phenobarbitone and primidone in epileptic patients.

Plasma, brain, lumbar CSF, skeletal muscle, skin and bone concentrations of phenytoin, phenobarbitone and primidone have been measured in specimens from patients undergoing temporal lobectomy for chronic epilepsy. A good correlation was found between the plasma and brain concentrations of each drug. Similarly, a good correlation was found between the plasma and CSF concentrations of each drug. Assuming that CSF is an ultrafiltrate of plasma, the percentage of phenytoin, phenobarbitone and primidone which was unbound in plasma was 10-14%, 43% and 81% respectively. Skeletal muscle concentrations of phenytoin and phenobarbitone and the skin concentration of phenytoin, also correlated with the plasma concentrations, but the remaining tissues did not give significant correlations.

Inhibition of phenytoin metabolism by other drugs used in epilepsy.

Phenytoin metabolism is saturable within its normal therapeutic range and, therefore, small changes in the activity of the enzyme can lead to marked changes in serum phenytoin concentrations. The anticonvulsant drugs sulthiame and pheneturide both inhibit the metabolism of phenytoin. The mechanism of this interaction appears to be different for these two drugs. Nortriptyline produces a small increase in serum phenytoin concentrations, but this is unlikely to be of clinical importance. Case reports suggest that both chlorpromazine and chloramphenicol inhibit phenytoin metabolism to a significant degree.

Effect of age, height, weight and sex on serum phenytoin concentration in epileptic patients.

1 Steady-state serum phenytoin concentrations were measured in adult epileptic patients receiving a maintenance dose of phenytoin (300 mg daily). 2 Serum phenytoin concentration showed a positive correlation with age. 3 Serum phenytoin concentration showed a negative correlation with body weight and with height. Multiple correlation analysis indicated that body weight influenced the concentration to a much greater degree than height. 4 When corrected for body weight and height, the serum phenytoin concentrations in women were lower than those in men, although the difference was not statistically significant. 5 Although each of these factors contributes to the interindividual variation in serum phenytoin concentrations, the contribution of each is small. Other factors, such as genetic differences and the effect of saturation kinetics, are much more important in determining steady-state concentrations. Adjusting the dose according to the age, weight and height of a patient would achieve only a marginal improvement in therapy.

Involuntary movements caused by phenytoin intoxication in epileptic patients.

The case histories of four patients who developed choreoathetoid movements during intoxication with phenytoin are presented. Drug intoxication was confirmed in each case by measuring the serum phenytoin concentration. Drug interactions were, in part, responsible for the occurrence of intoxication in three of them. Phenytoin intoxication is not always easy to recognize, particularly when nystagmus is minimal or absent, as in these four patients. The estimation of the serum phenytoin concentration is invaluable in this situation.

Phenytoin intoxication induced by sulthiame in epileptic patients.

Routine estimation of serum phenytoin levels in patients newly admitted to a Special Centre for Epilepsy showed that 40% of those receiving sulthiame in addition to phenytoin had levels in the toxic range. Four long-stay patients became drug intoxicated when sulthiame treatment was started. Sulthiame appears to inhibit the hepatic hydroxylation of phenytoin.