SIBUTRAMINE

 

• B. PROTEIN BINDING
• 1. In vitro protein binding of sibutramine and its two desmethyl metabolites, M1 and M2 is 97%, 94%, and 94%, respectively (Prod Info Meridia(R), 1997).
• 8.2.2 DISTRIBUTION KINETICS
• A. STEADY STATE LEVELS
• 1. Plasma concentrations of the two active metabolites reached steady-state within 4 days of dosing (Prod Info Meridia(R), 1997).
• 8.3 METABOLISM
• 8.3.1 METABOLISM SITES AND KINETICS
• A. THERAPEUTIC DOSE
• 1. Sibutramine undergoes extensive first pass metabolism in the liver, resulting in the formation of 2 active metabolites (Lean, 1997; Prod Info Meridia(R), 1997).
• 8.3.2 METABOLITES
• A. THERAPEUTIC DOSE
• 1. Two active metabolites, mono-desmethyl metabolite (M1) and di-desmethyl metabolite (M2), are formed by metabolism from cytochrome P450(3A4) in the liver (Prod Info Meridia(R), 1997; Stock, 1997).
• a. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6 (Prod Info Meridia(R), 1997).
• 8.4 EXCRETION
• 8.4.1 KIDNEY
• A. Approximately 77% of a single orally administered dose is excreted in the urine (Prod Info Meridia(R), 1997).
• 8.4.2 FECES
• A. Approximately 8% of a single orally administered dose is excreted in the feces (Prod Info Meridia(R), 1997).
• 8.5 ELIMINATION HALF-LIFE
• 8.5.2 METABOLITE
• A. THERAPEUTIC DOSE
• 1. The two active metabolites of sibutramine have long elimination half-lives of approximately 14 to 16 hours (Lean, 1997; Prod Info Meridia(R), 1997).
• 9.0 PHARMACOLOGY/TOXICOLOGY
• 9.1 PHARMACOLOGIC MECHANISM
• A. Sibutramine is a nonamphetamine appetite suppressant with some antidepressant properties. It appears to block neuronal uptake of norepinephrine, and to a lesser extent, serotonin and dopamine. It does NOT act via release of monoamine neurotransmitters and does NOT have affinity for their receptors (Stock, 1997; Luscombe et al, 1990). In normal volunteers, the drug was devoid of anticholinergic or central nervous system (CNS) depressant effects (Prod Info Meridia(R), 1997).
• B. In animal studies, rapid downregulation of cortical beta-receptors has been observed, and toxicologic testing, decreased feeding and weight reduction were noted (King & Devaney, 1988; Luscombe et al, 1990; Weintraub et al, 1991; Heal et al, 1992; Heal et al, 1992a).
• 12.0 REFERENCES
• 12.2 GENERAL BIBLIOGRAPHY
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• 11. Chyka PA & Seger D: Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Clin Toxicol 1997; 35:721-736.
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• 26. Heal DJ, Prow MR, Gosden J et al: A comparison of various antidepressant drugs demonstrates rapid desensitisation of a2-adrenoceptors exclusively by sibutramine hydrochloride. Psychopharmacol 1992; 107:497-502.
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• 33. Lean MEJ: Sibutramine--a review of clinical efficacy. Int J Obesity 1997; 21(suppl) 1):S30-S36.
• 34. Luscombe GP, Slater NA, Lyons MB et al: Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl. Psychopharmacology 1990; 100:345-349.
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• 46. Wallin JD & O'Neill WM: Labetalol. Arch Intern Med 1983; 143:485-490.
• 47. Weintraub M, Rubio A, Golik A et al: Sibutramine in weight control: A dose- ranging, efficacy study. Clin Pharmacol Ther 1991; 50:330-337.
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• 13.0 AUTHOR INFORMATION
• 13.1 CONTRIBUTOR(S) TO THIS DOCUMENT
• A. Original publication: 03/98
• 13.2 REVIEWERS
• A. Most recent revision: 03/98
• 13.3 LAST CONTRIBUTION DATE

o              A. List of contributors:

o              1.   Katherine M Hurlbut, MD

o              2.   POISINDEX(R) Editorial Staff

• 13.4 SPECIALTY BOARD
• A. Specialty Board: CNS DRUGS
• Refer to the POISINDEX EDITORIAL BOARD section for more information. (MG2142)

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