Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam.

Jochemsen, R.; Beusekom, B. R. Van; Spoelstra, P.; Janssens, A. R.; Breimer, D.D.

doi:10.1111/j.1365-2125.1983.tb01502.x

Cited by 37 publications

(12 citation statements)

References 36 publications

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“…However, at least in rats, substantial evidence is presented that in those in vivo situations where extensive biotransformation by aromatic nitroreduction was observed, the intestinal microflora was responsible for it rather than liver systems (Wheeler et al, 1975;Levin & Dent, 1982). An indication that in man the rate of aromatic nitroreduction is small too, may be given by the low clearance of the benzodiazepine derivative nitrazepam, the elimination of which is believed to depend solely on aromatic nitroreduction (Jochemsen et al, 1983). However, also with respect to this drug, the role of the intestinal microflora has been stressed for its clearance (Hewick & Shaw, 1978).…”

Section: Resultsmentioning

confidence: 99%

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Thijssen¹,

Baars²

1983

Brit J Clinical Pharma

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1 The pharmacokinetics and pharmacodynamics of racemic acenocoumarol (AC), the amino (AM) and acetamido (AA) derivative were investigated in healthy volunteers after administration of a single oral (10 mg) dose. 2 All three coumarins were rapidly absorbed from the gastrointestinal tract. The elimination half-lives were 10.9, 10.4, and 4.1 h, for AC, AM and AA, respectively. 3 After the oral administration of AC, no AM and AA was detected in the plasma, and less than 1% of the dose was recovered in the urine (0-24 h) as AM. 4 Renal clearance was the main route of elimination of AM and AA; the former by glomerular filtration, the latter by active excretion. 5 Binding to serum proteins was the highest for AC (1.52% free). AM and AA were less tightly bound (about 3% free). AM or AA did not interfere with the AC plasma protein binding. 6 The oral administration of AC resulted in a rise in prothrombin time with a maximum effect at 24 to 30 h. No anticoagulant activity was observed upon the administration of AM and AA. 7 The results indicate that the compounds AM and AA, if they are formed out of AC at all, do not contribute to the anticoagulant activity of AC.

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Section: Resultsmentioning

confidence: 99%

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Thijssen¹,

Baars²

1983

Brit J Clinical Pharma

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“…For nitrazepam, Jochemsen et al (1983b) reported no significant difference between the percentage free in 9 young (13.0% free) and 8 elderly subjects (13.9%). When the study was repeated in another group of 23 subjects aged 30 to 79 years, the average percentage free in subjects over 50 years was higher (14.3%) than in subjects under 50 years (13.1%).…”

Section: I3-blockersmentioning

confidence: 86%

Plasma Protein Binding of Drugs in the Elderly

Wallace

Verbeeck

1987

Clinical Pharmacokinetics

121

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Binding to plasma proteins can affect the pharmacokinetics and pharmacodynamics of drugs. Age is one of many factors which can affect plasma protein binding of drugs. Unfortunately, very few generalities can be drawn from the studies of the effect of age on protein binding. Whether age has an effect on protein binding is dependent not only on the drug, but also on the manner in which the study is conducted. Several studies involve patients with various disease states making assessment of the effect of age alone on protein binding difficult. Results of different studies on the same drug do not always agree--in one case finding no change in protein binding with age and in another, a significant increase or decrease in protein binding. Most drugs which exhibit increased binding (decreased free fraction) in elderly subjects are basic and tend to have a greater affinity for alpha 1-acid glycoprotein than for albumin. The list of drugs exhibiting decreased binding (increased free fraction) in the elderly is longer and includes both acidic and basic drugs. The impact of changes in protein binding with age is dependent on the magnitude of the change, on the pharmacokinetic characteristics of the drug and on its therapeutic index. Some changes, although statistically significant, are not likely to be of importance clinically. From the studies reviewed, the free fraction is changed by greater than 50% in the elderly for only a few drugs, e.g. acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate and zimeldine.

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“…Impairment of the rate of drug elimination in the elderly has been demonstrated for those benzodiazepines which are primarily oxidized (e.g. diazepam, chlordiazepoxide, desalkylflurazepam and desmethyldiazepam) (Divoll Allen et al, 1980;Greenblatt et al, 1980aKlotz et al, 1975;Klotz & Muller-Seydlitz, 1979;Roberts et al, 1978) and for nitrazepam (Jochemsen et al, 1983b;Kangas et al, 1979). Age, on the other hand, has little, if any, effect on the disposition of benzodiazepines, for which drug conjugation is the primary metabolic step Greenblatt et al, 1979Greenblatt et al, , 1980bKrauss et al, 1978;Shull et al, 1976) Benzodiazepines are frequently prescribed for elderly patients and age related changes in clinical effects may be due to alterations in protein binding, distribution or clearance.…”

Section: Results)mentioning

confidence: 99%

Pharmacokinetics of brotizolam in the elderly.

Jochemsen¹,

Nandi²,

Corless³

et al. 1983

Brit J Clinical Pharma

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1 Disposition of brotizolam in patients aged 71-93 years was compared with that of healthy young subjects aged 21-26 years.2 The mean elimination half-life of brotizolarh was about twice as long in the elderly as in the young subjects: 9.3 (4.0-19.5) h and 4.8 (3.1-6.3) h respectively. Increase in elimination half-life was attributable to a decrease in hepatic clearance i.e. 40 (20-58) ml/min in the elderly and 109 (77-156) ml/min in the young. Volume of distribution and protein binding were the same with mean values of 0.56 (0.45-0.72) 1/kg and 9.0 (6.8-11.9) No in the elderly and 0.63 (0.40-0.77) 1/kg and 8.4 (7.5-9.4)% in the young. 3 Absorption rate of brotizolam was relatively slow in the elderly with a mean peak time of 1.7 h compared with 1.1 h in the young. Mean bioavailability was almost 70% for both groups. Normalized for body weight and dose (0.25 mg) mean peak concentrations were 247 (137-395) ng ml-' kg in the young and 343 (251-446) ng ml-1 kg in the elderly.4 It is unlikely that substantial drug accumulation will occur if elderly patients ingest 0.25 mg brotizolam nightly.

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Effect of age and liver cirrhosis on the pharmacokinetics of nitrazepam.

Cited by 37 publications

References 36 publications

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Plasma Protein Binding of Drugs in the Elderly

Pharmacokinetics of brotizolam in the elderly.

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