Distribution and Elimination of the Glycosidase Inhibitors 1-Deoxymannojirimycin and N-Methyl-1-Deoxynojirimycin in the Rat in Vivo

Authors: Faber E.D.¹; Oosting R.²; Neefjes J.J.³; Ploegh H.L.³; Meijer D.K.F.²

Source: Pharmaceutical Research, Volume 9, Number 11, November 1992 , pp. 1442-1450(9)

Publisher: Springer

Abstract:

We studied the pharmacokinetics of two synthetic derivatives of 1-deoxynojirimycin in the rat after intravenous administration. The mannosidase IA/B inhibitor 1-deoxymannojirimycin and the glucosidase inhibitor N-methyl- 1-deoxynojirimycin exhibited minimal plasma protein binding and showed a rapid biphasic plasma disappearance, with an initial t_1/2 of 3.0 and 4.5 min, respectively, and a terminal t_1/2 of 51 and 32 min, respectively. For both compounds renal excretion is the major route of elimination. After 120 min, 52% of the dose of 1-deoxymannojirimycin and 80% of the dose of N-methyl- 1-deoxymannojirimycin was recovered unchanged from the urine, whereas only 4.9 and 0.2%, respectively, of the dose was excreted in bile. Urinary clearance of 1-deoxymannojirimycin was similar to the glomerular filtration rate. In contrast, urinary clearance of N-methyl- 1-deoxynojirimycin was two to three times higher than the glomerular filtration rate, indicating active tubular secretion. Ligation of the renal vessels decreased the total-body clearance of 1-deoxymannojirimycin and N-methyl- 1-deoxynojirimycin 18- and 24-fold, respectively. Neither alkalinization of the urine by infusion of bicarbonate solutions nor forced diuresis altered the renal excretion rate of these compounds, implying the absence of tubular reabsorption. At 120 min, the amounts of 1-deoxymannojirimycin in liver and kidney were 2.1 and 1.1% of the dose, respectively, while small intestine, stomach, and heart contained only 0.9, 0.6 and 0.1%. Less than 1% of the dose of N-methyl-1-deoxynojirimycin was found in the collected organs 2 hr after injection. At the same time point, the kidney/plasma concentration ratio of N-methyl- 1-deoxynojirimycin was 10-fold higher than in other tissues, whereas for 1-deoxymannojirimycin it was only 2- to 3-fold higher in kidney, indicating a more persistent general tissue retention of 1-deoxymannojirimycin.

Keywords: 1-deoxymannojirimycin; N-methyl-1-deoxynojirimycin; glycosidase inhibitors; pharmacokinetics; in vivo; intravenous administration

Language: English

Document Type: Regular paper

Affiliations: 1: Department of Pharmacology and Therapeutics, University Centre for Pharmacy, University of Groningen, Ant. Deusinglaan 2, 9713 AW Groningen, The Netherlands. To whom correspondence should be addressed. 2: Department of Pharmacology and Therapeutics, University Centre for Pharmacy, University of Groningen, Ant. Deusinglaan 2, 9713 AW Groningen, The Netherlands. 3: The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Publication date: 1992-11-01

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• In this Subject: Pharmacology
• By this author: Faber E.D. ;  Oosting R. ;  Neefjes J.J. ;  Ploegh H.L. ;  Meijer D.K.F.

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