Disposition of Lorazepam in Diabetes: Differences Between Patients Treated with Beef/pork and Human Insulins

Overview

Journal Eur J Clin Pharmacol

Specialty Pharmacology

Date 1995 Jan 1

PMID 7589050

Authors

R J Herman

A Chaudhary

C B Szakacs

D Woo

R Lane

M A Boctor

Affiliations

Soon will be listed here.

Abstract

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.

References

Daintith H, Stevenson I, OMalley K . Influence of diabetes mellitus on drug metabolism in man. Int J Clin Pharmacol Biopharm. 1976; 13(1):55-8. View

Sochor M, Baquer N, McLean P . Regulation of pathways of glucose metabolism in kidney. The effect of experimental diabetes on the activity of the pentose phosphate pathway and the glucuronate-xylulose pathway. Arch Biochem Biophys. 1979; 198(2):632-46. DOI: 10.1016/0003-9861(79)90541-1. View

Vega P, Gaule C, Sanchez E, Del Villar E . Inhibition and activation of UDP-glucuronyltransferase in alloxanic-diabetic rats. Gen Pharmacol. 1986; 17(6):641-5. DOI: 10.1016/0306-3623(86)90293-4. View

Morrison M, Hawksworth G . Glucuronic acid conjugation by hepatic microsomal fractions isolated from streptozotocin-induced diabetic rats. Biochem Pharmacol. 1984; 33(23):3833-8. DOI: 10.1016/0006-2952(84)90048-0. View

RUELIUS H . Comparative metabolism of lorazepam in man and four animal species. J Clin Psychiatry. 1978; 39(10 Pt 2):11-5. View

Herman R, Van Pham J, Szakacs C . Disposition of lorazepam in human beings: enterohepatic recirculation and first-pass effect. Clin Pharmacol Ther. 1989; 46(1):18-25. DOI: 10.1038/clpt.1989.101. View

Tattersall R, Gill G . Unexplained deaths of type 1 diabetic patients. Diabet Med. 1991; 8(1):49-58. DOI: 10.1111/j.1464-5491.1991.tb01516.x. View

Olefsky J . The insulin receptor. A multifunctional protein. Diabetes. 1990; 39(9):1009-16. DOI: 10.2337/diab.39.9.1009. View

Yamaoka K, Nakagawa T, Uno T . Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm. 1978; 6(2):165-75. DOI: 10.1007/BF01117450. View

10.

Tozer T, Gambertoglio J, Furst D, Avery D, Holford N . Volume shifts and protein binding estimates using equilibrium dialysis: application to prednisolone binding in humans. J Pharm Sci. 1983; 72(12):1442-6. DOI: 10.1002/jps.2600721218. View

11.

Greenblatt D, Schillings R, KYRIAKOPOULOS A, Shader R, Sisenwine S, Knowles J . Clinical pharmacokinetics of lorazepam. I. Absorption and disposition of oral 14C-lorazepam. Clin Pharmacol Ther. 1976; 20(3):329-41. DOI: 10.1002/cpt1976203329. View

12.

Crom W, Webster S, Bobo L, Teresi M, Relling M, Evans W . Simultaneous administration of multiple model substrates to assess hepatic drug clearance. Clin Pharmacol Ther. 1987; 41(6):645-50. DOI: 10.1038/clpt.1987.90. View

13.

Chaudhary A, Lane R, Woo D, Herman R . Multiple-dose lorazepam kinetics: shuttling of lorazepam glucuronide between the circulation and the gut during day- and night-time dosing intervals in response to feeding. J Pharmacol Exp Ther. 1993; 267(3):1034-8. View

14.

Rosenzweig S, Zetterstrom C, Benjamin A . Identification of retinal insulin receptors using site-specific antibodies to a carboxyl-terminal peptide of the human insulin receptor alpha-subunit. Up-regulation of neuronal insulin receptors in diabetes. J Biol Chem. 1990; 265(29):18030-4. View

15.

Sesti G, Marini M, Montemurro A, Borboni P, Di Cola G, Bertoli A . Evidence that human and porcine insulin differently affect the human insulin receptor: studies with monoclonal anti-insulin receptor antibodies. J Endocrinol Invest. 1991; 14(11):913-8. DOI: 10.1007/BF03347115. View

16.

Hinohara Y, Takanashi S, Nagashima R, Shioya A . Glucuronic acid pathway in alloxan diabetic rabbits. (I). Urinary excretion of metabolites related to the glucuronic acid pathway. Jpn J Pharmacol. 1974; 24(6):869-78. DOI: 10.1254/jjp.24.869. View

17.

Ruiz-Cabello F, Erill S . Abnormal serum protein binding of acidic drugs in diabetes mellitus. Clin Pharmacol Ther. 1984; 36(5):691-5. DOI: 10.1038/clpt.1984.241. View

18.

Wilkinson G, SHAND D . Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975; 18(4):377-90. DOI: 10.1002/cpt1975184377. View

19.

McClain D, Maegawa H, Thies R, Olefsky J . Dissection of the growth versus metabolic effects of insulin and insulin-like growth factor-I in transfected cells expressing kinase-defective human insulin receptors. J Biol Chem. 1990; 265(3):1678-82. View

20.

Naranjo C, Sellers E, Giles H, Abel J . Diurnal variations in plasma diazepam concentrations associated with reciprocal changes in free fraction. Br J Clin Pharmacol. 1980; 9(3):265-72. PMC: 1429881. DOI: 10.1111/j.1365-2125.1980.tb04836.x. View