The Effects of Age and Liver Disease on the Disposition and Elimination of Diazepam in Adult Man

Klotz, Ulrich; Avant, George R.; Hoyumpa, Anastacio M.; Schenker, Steven; Wilkinson, Grant R.

doi:10.1097/00132586-197602000-00007

Cited by 70 publications

(100 citation statements)

References 13 publications

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“…A larger free fraction in females as compared to males was also observed for chlordiazepoxide (Roberts et al, 1979) and diazepam (Abel et al, 1979). On the other hand, Greenblatt and coworkers only found a sex difference in protein binding for diazepam in subjects with renal failure (Greenblatt et al, 1978), but not in healthy volunteers (Greenblatt et al, 1980 Greenblatt et al (1979), but Klotz et al (1975) found no effect of smoking on diazepam clearance.…”

Section: Resultsmentioning

confidence: 93%

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

Jochemsen¹,

Graaff²,

Boeijinga³

et al. 1982

Brit J Clinical Pharma

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1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and in females in either phase of the cycle. The elimination half-life was 27.3 + 1.3 h in males, 27.7 + 1.5 h in females in the follicular phase and 29.6 + 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 ± 2.7 ml/min, 58.2 + 3,3 and 55.8 ± 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 + 2.3 and 31.2 + 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 + 4.6 and 45.6 ± 4.1 ml/min) was significantly lower than in males (P < 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 ± 0.1%) to females in the luteal phase of the cycle (12.4 + 0.5%) to females using OC-steroids (13.5 ± 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (C; = 323 + 30 ml/min in females using OC-steroids, 530 + 37 ml/min in males and 459 + 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have higher steady state levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.

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Section: Resultsmentioning

confidence: 93%

Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam.

Jochemsen¹,

Graaff²,

Boeijinga³

et al. 1982

Brit J Clinical Pharma

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“…The age dependent increase in the disposition half-life for lignocaine cannot be attributed to a reduction in activity of drug-metabolizing enzymes since the total plasma clearance for lignocaine remained constant (Table 3). Klotz, Avant, Hoyumpa, Schenker & Wilkinson (1975) have reported that even though the disposition half-life of diazepam is strikingly agedependent the plasma clearance remains essentially constant throughout adult life. The drug clearance value provides the best index of the body's ability to remove drug.…”

Section: Discussionmentioning

confidence: 99%

Lignocaine kinetics in cardiac patients and aged subjects.

Nation¹,

Triggs²,

Selig³

1977

Brit J Clinical Pharma

158

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1 The pharmacokinetics following long term intravenous infusion of lignocaine to cardiac patients have been examined. 2 Plasma levels and half‐lives of lignocaine and monoethylglycinexylidide (MEGX) showed wide inter‐patient variability. 3 Toxicity reactions to therapy were associated with elevated lignocaine and/or MEGX plasma levels. 4 In a separate study the effect of age on the pharmacokinetics of lignocaine was examined using bolus doses (50 mg) of the drug to young and aged subjects. 5 Elderly subjects had significantly longer half‐lives for lignocaine compared to younger individuals although no change in plasma clearance occurred. 6 The drug appeared to distribute differently in the aged as reflected by significantly increased apparent volumes of distribution. 7 The 24 h urinary recovery of the major metabolite (total 4‐hydroxyxylidine) showed a significant reduction in the elderly when compared to the young. 8 The clinical significance of these studies with respect to lignocaine therapy has been discussed.

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“…Subjects remained in the supine position for the first 10 h, except at the time of the test. Concentrations of diazepam were assayed in the different plasma samples by a specific and sensitive gaschromatographic procedure (Klotz, Avant, Hoyumpa, Schenker & Wilkinson, 1975 (Berman & Weis, 1974). This model and its pharmacokinetic parameter have been well described (Riegelman, Loo & Rowland, 1968).…”

Section: Physical Exercise and Disposition Of Diazepammentioning

confidence: 99%

“…Hepatic elimination can be modified by changes in hepatic blood flow (Rowland, Benet & Graham, 1973) and during exercise this flow decreases. Since diazepam belongs to the group of drugs whose elimination is independent of the liver blood flow (Klotz et al, 1975), it is not surprising that its total body clearance (Cl) and its half-life of elimination (TO/) were unaffected by physical exercise. In addition, at the different times of blood sampling no significant increases or decreases in the plasma levels could be observed after a maximal work-load lasting for 5 min.…”

Section: Physical Exercise and Disposition Of Diazepammentioning

confidence: 99%