Disposition Of Lorazepam Research Articles

Disposition of lorazepam in diabetes: differences between patients treated with beef/pork and human insulins.

The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml.min-1.kg-1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.

Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect.

The effects of neomycin and cholestyramine on the disposition of lorazepam was examined in seven healthy drug-free men. Half-life as determined for the oral route was, in all subjects, 15% to 35% less than that determined for the intravenous route. Free oral clearance was slightly but not significantly less than free systemic clearance, but the ratio of the AUC of lorazepam glucuronide corrected for dose was twofold greater by the oral route. Urinary recoveries also differed (71.6% and 50.4%, oral versus intravenous). Neomycin and cholestyramine treatment resulted in a 19% to 26% reduction in half-life attendant on a 34% increase in free oral clearance and a 24% increase in free systemic clearance. This suggests that lorazepam undergoes significant enterohepatic recirculation in human beings and that there exists an extrahepatic pathway, at least for the intravenous route. Since pharmacokinetic measurements do not take these physiologic processes into account, the drug cannot properly be used as a marker of conjugative metabolism.

Altered elimination of desmethyldiazepam in the elderly.

British Journal of Clinical PharmacologyVolume 7, Issue 1 p. 119-120 Free Access Altered elimination of desmethyldiazepam in the elderly. U Klotz, U KlotzSearch for more papers by this authorP Muller-Seydlitz, P Muller-SeydlitzSearch for more papers by this author U Klotz, U KlotzSearch for more papers by this authorP Muller-Seydlitz, P Muller-SeydlitzSearch for more papers by this author First published: January 1979 https://doi.org/10.1111/j.1365-2125.1979.tb00908.xCitations: 28AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References BOSTON COLLABORATIVE SURVEILLANCE DRUG PROGRAM (1973). Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N. Engl. J. Med., 288, 277– 280. Gibaldi, M., Nagashima, R. & Levy, G. (1969). Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci., 58, 193– 197. Klotz, U., Avant, G.R., Hoyumpa, A., Schenker, S. & Wilkinson, G.R. (1975). Effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. clin. Invest., 55, 347– 359. Klotz, U., Antonin, K.H. & Bieck, P.R. (1976). Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur. J. clin. Pharmac., 10, 121– 126. Kraus, J.W., Desmond, P.V., Marshall, J.P., Johnson, R.F., Schenker, S. & Wilkinson, G.R. (1978). The effects of aging and liver disease on the disposition of lorazepam in man. Clin. Pharmac. Ther., 24, 411– 419. Randall, L.O., Scheckel, C.L. & Banzinger, R.F. (1965). Pharmacology of the metabolites of chlordiazepoxide and diazepam. Curr. Ther. Res., 7, 590– 606. Roberts, R.K., Wilkinson, G.R., Branch, R.A. & Schenker, S. (1978). The effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide. Gastroenterology, 75, 479– 485. Schwartz, M.A., Koechlin, B.A., Postma, E., Palmer, S. & Krol, G. (1965). Metabolism of diazepam in rat, dog, and man. J. Pharmac. exp. Ther., 149, 423– 435. Shader, R.I., Greenblatt, D.J., Harmatz, J.S., Franke, K. & Koch-Weser, J. (1977). Absorption and disposition of chlordiazepoxide in young and elderly male volunteers. J. clin. Pharmac., 17, 709– 718. Shull, H.J., Wilkinson, G.R., Johnson, R.F. & Schenker, S. (1976). Normal elimination of oxazepam in acute viral hepatitis and cirrhosis. Ann. intern. Med., 84, 420– 425. Westlake, W.J. (1970). Time integral of drug concentration in the central (plasma) compartment. J. pharm. Sci., 59, 722– 723. Citing Literature Volume7, Issue1January 1979Pages 119-120 ReferencesRelatedInformation

Effects of aging and liver disease on disposition of lorazepam.

The disposition of lorazepam after intravenous administration (2 mg) was investigated in patients with alcoholic cirrhosis and acute viral hepatitis, and compared to that in normal subjects ranging in age from 15 to 73 yr. No statistically significant age‐dependent relationships in the drug's pharmacokinetic parameters were observed. Cirrhosis was associated with a doubling of the mean elimination half‐life (21.7 ± 7.6 to 41.2 ± 24.5 hr). This was due to a similar increase in the volume of distribution of lorazepam, caused by a reduction in the extent of the drug's plasma binding (88.6 ± 2.5 from 93.2 ± 1.8). No changes in systemic plasma clearance of either the unbound (about 11 ml/min/kg) or bound plus unbound (about 0.75 ml/min/kg) lorazepam, or urinary recovery of conjugated drug (about 50%) were detected. In contrast, there were no significant changes in the kinetics of lorazepam in the patients with acute viral hepatitis. Comparison of lorazepam's systemic plasma clearance in the liver disease patients in whom studies with antipyrine and chlordiazepoxide had also been performed indicated impairment in their values but this was not the case for lorazepam. It is concluded that the degree of impairment, if any, in the metabolism of lorazepam in patients with liver disease is considerably less than that of certain other drugs including related benzodiazepines. Aging also does not lead to alterations either in distribution or metabolism as have been observed with other benzodiazepines. It is speculated that these observations may reflect characteristics of the drugs associated with their metabolic fate, i.e., glucuronidation or oxidative biotransformation.