M2

Figure 1 Dethylpropion and its major metabolites.

6.18.6.2.6 Phendimetrazine

6.18.6.2.6.1 Mechanism of action

Phendimetrazine is yet another sympathomimetic, CNS-stimulant type of anorexiant. After oral administration it shows significant metabolism to phenmetrazine (Figure 2). Differences in the in vivo effects of phendimetrazine and phenmetrazine, which depend on the route of administration, have led to the speculation that phendimetrazine might actually be a prodrug and that one of its metabolites is the active compound.11

Examination of phendimetrazine for effects on the uptake or release of DA, NE, and 5-HT revealed no interaction of the parent compound with either uptake or release of these monoamines.11 Phendimetrazine is a racemic mixture of the trans configuration, producing both trans isomers of phenmetrazine when metabolized in vivo. Unlike the parent compound, both of these isomers affected both NE and DA release (Table 5).11 In this regard the (+) isomer appeared to be the more potent isomer. Thus, it appears likely that biologic effects of phendimetrazine are due primarily to the effects of the metabolite phenmetrazine on central NE and DA release.

6.18.6.2.6.2 Indications

Phendimetrazine is approved as a short-term (a few weeks) adjunct for the treatment of obesity in a weight reduction plan based on caloric restriction.

6.18.6.2.6.3 Issues, side effects, and contraindications

The principal issues with phendimetrazine are the same as for the other CNS stimulants, e.g., tolerance to the anorectic effects, CNS stimulation/excitation, and increased blood pressure.

6.18.6.2.7 Sibutramine

6.18.6.2.7.1 Mechanism of action

Sibutramine is believed to produce its therapeutic effects through the inhibition of the reuptake of NE, 5-HT, and DA. Unlike the other anorectic agents discussed above, it does not cause the release of any of these monoamines. In vivo sibutramine is N-demethylated to form both desmethylsibutramine and didesmethylsibutramine (Figure 3).

While sibutramine has some effect on the reuptake of the monoamine neurotransmitters, most of the activity appears to reside in the metabolites. Sibutramine is a racemic mixture that produces enantiomers of both demethylated metabolites in vivo. Glick et al}z have examined the parent compound as well as these metabolites for their effects on monoamine uptake (Table 6). It appears likely that the pharmacologic effects of sibutramine in vivo are due to its metabolites, and that there is a clear selectivity between the isomers, with the R-isomer being the more potent.

Phendimetrazine Phenmetrazine

'denotes chiral centers

Figure 2 Metabolism of phendimetrazine to phenmetrazine.

Table 5 Comparison of uptake inhibition and release by phendimetrazine and phenmetrazine
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