Chlordiazepoxide and oxazepam disposition in cirrhosis

1 The effect of liver cirrhosis on plasma clearance and metabolite profile of i.v. administered antipyrine was studied in 23 patients wth alcoholic liver cirrhosis (age years) and 17 healthy subjects (age 28-55 years). 2 Liver volume was also measured and was found to be larger in patients than in controls, mean values being 1.86 and 1.36 1 respectively. 3 The elimination half-life of antipyrine in patients with alcoholic liver cirrhosis was significantly longer than in the healthy subjects (P < 0.001). Mean values were 39.9 and 10.1 h respectively. 4 Alcoholic liver cirrhosis had no effect on the apparent volume of distribution of antipyrine, but antipyrine plasma clearance was substantially reduced in the patients.Mean clearance values (ranges) were 13.5 (9.3-22.8) ml/min in the patients and 49.3 (31.1-103) m/min in healthy subjects. 5 Normalization of antipyrine plasma clearance for liver volume resulted in an only slightly increased distinction between patients and healthy subjects, mean values (ranges) being 7.8 (3.3-13.0) ml min-' 171 and 36.1 (21.9-35.9) ml min-1 1-1 respectively. 6 The cumulative renal excretion of 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was significantly lower in patients with alcoholic liver cirrhosis than in healthy subjects, as was the total recovery of antipyrine and major metabolites from urine. Mean values were 15.0, 8.4 and 41.2% of dose in the patients respectively and 24.3, 25.8 and 68.9% of dose in the control subjects. Excreted amounts of total and unconjugated 3-hydroxymethylantipyrine (HMA) and of unchanged antipyrine were the same in the two groups.7 Clearance for production of all three major metabolites of antipyrine (CLm) was markedly reduced in patients with alcoholic cirrhosis, while the rate of formation of NORA was significantly more reduced than the rates of formation of OHA and HMA.Mean values for CLOHA, CLNORA and CLHMA were: 2.6, 1.4 and 2.0 ml/min respectively in the patients and 12.9, 13.2 and 7.9 ml/min in the healthy subjects. 8 The results of this study show that antipyrine metabolism is severely impaired in patients with alcoholic liver cirrhosis. However, as the rates of formation of antipyrine metabolites were not reduced to the same extent, different isoenzymes of the cytochrome P-450 system may be differently affected by alcoholic liver cirrhosis.

Section: Discussionmentioning

confidence: 99%

Antipyrine clearance and metabolite formation in patients with alcoholic cirrhosis.

Teunissen¹,

Spoelstra²,

Koch³

et al. 1984

“…Benzodiazepines that are primarily oxidized (diazepam, desmethyldiazepam, chlordiazepoxide and desalkylflurazepam) generally exhibit substantially longer elimination half-lives in the elderly and in patients with liver disease. This is due to a lower metabolic clearance and/or a larger volume of distribution (Divoll Allen et al, 1980;Greenblatt et al, 1980aGreenblatt et al, , 1981Klotz et al, 1975;Klotz & Muller-Seydlitz, 1979;Sellers et al, 1979 (Divoll etal., 1981;Greenblatt etal., 1979Greenblatt etal., , 1980bKrauss et al, 1978;Shull et al, 1976). The elimination half-life of lorazepam was however significantly increased in patients with liver cirrhosis due to an increase in volume of distribution (Krauss et al, 1978).…”

Section: Alcoholic Liver Cirrhosismentioning

confidence: 99%

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

Jochemsen¹,

Beusekom²,

Spoelstra³

et al. 1983

1 The effect of age and liver cirrhosis on the pharmacokinetics of i.v. administered nitrazepam was studied in nine healthy relatively young subjects (age 22-49 years), eight healthy elderly (age [67][68][69][70][71][72][73][74][75][76] years) and 12 patients with alcoholic liver cirrhosis (age 39-66 years).2 The elimination half-life of nitrazepam in the elderly subjects was longer than in the young ones but the difference did not reach statistical significance. Mean values (ranges) were 38 (26-64) h and 26 (19-31) h respectively. 3 The increase in elimination half-life was primarily due to an increase in volume of distribution, mean values (ranges) being 2.93 (1.96-5.33) 1/kg and 1.89 (1.44-2.23) 1/kg in the elderly and young groups respectively (P < 0.05).4 The protein unbound fraction of nitrazepam tended to be higher in the elderly subjects, although the difference between the two age groups was not significant: 13.9 (11.5-15.4) % and 13.0 (11.0-15.9) % in elderly and young respectively.5 Age had no effect on the clearance of total nitrazepam nor on the clearance of unbound nitrazepam (intrinsic clearance). Mean values (ranges) were 63 (50-87) ml/min and 489 (377-635) ml/min in the young and 64 (47-91) ml/min and 456 (348-652) ml/min in the elderly subjects respectively. 6 There were no significant differences in elimination half life, clearance and volume of distribution between patients with alcoholic liver cirrhosis and the total of healthy subjects of both age groups, mean values (ranges) being 31 (21-55) h, 59(26-85) ml/min and 2.17 (1.57-3.22) 1/kg respectively in patients and 31 (19-64) h, 63(47-91) ml/min and 2.38 (1.44-5.33) 1/kg in healthy subjects. 7 The protein unbound fraction of nitrazepam was substantially higher in the patient group: 18.9 (14.8-30.3) % as compared to 13.8 (11.0-15.9) % in the healthy subjects (P < 0.001). 8 Clearance calculated relative to unbound nitrazepam (intrinsic clearance) was significantly lower in the patient group: 320(163-482) ml/min as compared to healthy subjects, 472 (348-652) ml/min (P <0.001).9 The results of this study indicate that nitrazepam action following single dose administration may be more persistent in elderly than in young people; however, steady state levels of total and unbound nitrazepam during nightly intake of the drug will not be affected by age. On the other hand, steady state levels of unbound nitrazepam in patients with liver cirrhosis will generally be about 35% higher than in healthy subjects.

“…The effect of liver cirrhosis on drug disposition has been studied for several benzodiazepines and differential effects have been observed. Chlordiazepoxide and diazepam, benzodiazepines that are primarily oxidized, exhibit much longer elimination half-lives in patients with liver cirrhosis than in age-matched controls, due to a lower metabolic clearance and a large volume of distribution (Klotz et al, 1975;Roberts et al, 1978;Sellers et al, 1979). On the other hand, liver cirrhosis has no influence on the metabolic clearance of oxazepam and lorazepam, benzodiazepines of which the primary biotransformation step is a conjugation reaction (Krauss et al, 1978;Sellers et al, 1979;Shull et al, 1976).…”

Section: Experimental Designmentioning

confidence: 99%

“…Chlordiazepoxide and diazepam, benzodiazepines that are primarily oxidized, exhibit much longer elimination half-lives in patients with liver cirrhosis than in age-matched controls, due to a lower metabolic clearance and a large volume of distribution (Klotz et al, 1975;Roberts et al, 1978;Sellers et al, 1979). On the other hand, liver cirrhosis has no influence on the metabolic clearance of oxazepam and lorazepam, benzodiazepines of which the primary biotransformation step is a conjugation reaction (Krauss et al, 1978;Sellers et al, 1979;Shull et al, 1976). The elimination half-life of lorazepam, however, was significantly prolonged in patients with liver cirrhosis, which was found to be due to a larger volume of distribution (Krauss et al, 1978 La farmacocinetica de brotizolam oral (0,5 mg) se estudi6 en pacientes de sexo masculino con cirrosis hepatica (pacientes) y en otros enfermos (control) similares en cuanto a edad, peso, costumbres fumadoras y bebedoras.…”

Section: Experimental Designmentioning

confidence: 99%

“…In the last few years, the influence of liver disease has been studied for several benzodiazepines and differential effects have been observed. The disposition of benzodiazepines which are primarily oxidized is quite strongly affected, resulting in a significantly prolonged elimination half-life (Klotz et al, 1975;Roberts et al, 1978;Sellers et al, 1979); on the other hand, liver disease has little effect on the disposition of benzodiazepines that are primarily conjugated (Krauss et al, 1978;Sellers et al, 1979;Shull et al, 1976).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.

Jochemsen¹,

Joeres²,

Wesselman³

et al. 1983

1 Disposition of oral brotizolam (0.5 mg) was studied in male patients with liver cirrhosis (patients) and in other patients (control) matched for age, weight, smoking and drinking habits. 2 Absorption of brotizolam was relatively rapid in both groups with a median peak time (range) of 1.0 (0.5-2.0) h. Peak concentrations were also similar with median values of 7.1 (3.2-10.7) ng/ ml in patients and 9.4 (2.9-19.0 ng/ml) in controls. 3 Elimination half-life was longer in patients than in controls. The median values were 12.8 (9.4-25) h and 6.9 (4.4-8.4) h respectively (P < 0.01). In two patients hardly any drug elimination was observed, indicating severe impairment of drug metabolizing activity. The prolongation of the elimination half-life was likely to be due to a decrease in clearance (45 ml/min in patients compared with 64 m/min in controls), and an increase in volume of distribution (0.62 1/kg and 0.39 1/kg respectively).4 Median values of protein unbound fraction of brotizolam were 9.2 (7.8-10.4) % in controls and 12.4 (10.4-18.9) % in patients. Clearance of unbound drug was 612 ml/min and 380 ml/min respectively.