Pharmacokinetics of reboxetine enantiomers in the dog

Frigerio, E.; Benecchi, A.; Brianceschi, G; Pellizzoni, C.; Poggesi, Italo; Benedetti, Μ. Strolin; Dostert, P.

doi:10.1002/(sici)1520-636x(1997)9:3<303::aid-chir17>3.0.co;2-r

Cited by 15 publications

(6 citation statements)

References 3 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the R,R ‐enantiomer did not alter supine or standing systolic or diastolic blood pressure compared with placebo. These data, in conjunction with the preclinical pharmacologic data, 6 , 7 , 8 , 9 , 11 suggest that the S,S ‐enantiomer is responsible for the hemodynamic, therapeutic, and adverse effects observed in humans during reboxetine treatment.…”

Section: Discussionmentioning

confidence: 80%

“…In preclinical studies, the S,S ‐enantiomer was more potent than the R,R ‐enantiomer in inhibiting both reserpine‐induced blepharospasm and norepinephrine reuptake in mice (data on file, Pharmacia & Upjohn, Milan, Italy). The pharmacokinetic properties of the two enantiomers have been investigated in animals 6 , 7 , 8 and found to be quantitatively different, with concentrations of the R,R ‐enantiomer higher than those of the S,S counterpart. The pharmacokinetic properties of the reboxetine enantiomers have also been investigated in healthy male volunteers, and the maximum plasma concentration (C max ) and the area under the plasma concentration–time curve (AUC) values for the R,R ‐enantiomer were approximately two times higher than those for the S,S ‐enantiomer.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Hemodynamic effects of reboxetine in healthy male volunteers*

Denolle¹,

Pellizzoni²,

Jannuzzo³

et al. 1999

Clin Pharmacol Ther

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

Hemodynamic effects of reboxetine in healthy male volunteers*

Denolle¹,

Pellizzoni²,

Jannuzzo³

et al. 1999

Clin Pharmacol Ther

View full text Add to dashboard Cite

show abstract

“…The pharmacokinetics of reboxetine enantiomers in plasma and urine samples has been assessed in dogs following oral treatments of 10 mg/kg reboxetine and 5 mg/kg of (R,R)-or (S,S)-reboxetine (Frigerio et al, 1997). Plasma and urinary levels of reboxetine enantiomers were monitored up to 48 h postdosing.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs

Ding

Lin

Garza

et al. 2003

Synapse

View full text Add to dashboard Cite

Reboxetine is a specific norepinephrine transporter (NET) inhibitor and has been marketed in several countries as a racemic mixture of the (R,R) and (S,S) enantiomers for the treatment of depression. Its methyl analog (methylreboxetine, MRB) has been shown to be more potent than reboxetine itself. We developed a nine-step synthetic procedure to prepare the normethyl precursor, which was used to synthesize [11C]O-methylreboxetine ([11C]MRB). We also developed a convenient resolution method using a chiral HPLC column to resolve the racemic precursor to obtain enantiomerically pure individual precursors that lead to the individual enantiomers (R,R)-[11C]MRB and (S,S)-[11C]MRB. Here we report an evaluation of the racemate and individual enantiomers of [11C]MRB as radioligands for PET imaging studies of NET systems in baboons both in brain and in peripheral organs. The relative regional distribution of the radioactivity after injection of [11C]MRB in baboon brain is consistent with the known distribution of NET. For a NET-poor region such as striatum, there were no significant changes in the striatal uptakes with and without the nisoxetine pretreatment. In contrast, a significant blocking effect was observed in NET-rich regions such as thalamus and cerebellum after injection of racemic [11C]MRB, with an even more dramatic effect after injection of (S,S)-[11C]MRB. These results, along with the fact that there was no regional specificity and no blocking effect by nisoxetine for (R,R)-[11C]MRB, suggest the enantioselectivity of MRB in vivo, consistent with previous in vitro and in vivo studies in rodents. PET studies of baboon torso revealed a blocking effect by desipramine only in the heart, a NET-rich organ, after injection of (S,S)-[11C]MRB, but not the (R,R)-isomer. These studies demonstrate that the use of (S,S)-[11C]MRB would allow a better understanding of the role that NET plays in living systems.

show abstract

“…All of them are HPLC methods, which require very expensive chiral stationary phases [23] or complicated derivatization procedures [24,25]. These analytical methods have been subsequently used for pharmacokinetic studies in rat and dog plasma [16,27].…”

Section: Introductionmentioning

confidence: 60%

Separation of reboxetine enantiomers by means of capillary electrophoresis

et al. 2002

View full text Add to dashboard Cite

The novel antidepressant reboxetine, a selective norepinephrine reuptake inhibitor, is increasingly used in the treatment of different forms of major depression. Reboxetine is a chiral compound, and is marketed as a racemic mixture of (R,R)- and (S,S)-reboxetine; however, the pharmacokinetic and toxicological profiles of the two enantiomers are rather different. For this reason, a simple capillary electrophoretic method for the separation of reboxetine enantiomers has been developed. Sulfobutyl ether-beta-cyclodextrin was chosen as the chiral selector, and several parameters, such as cyclodextrin and buffer concentration, buffer pH and capillary temperature were investigated in order to obtain good separation and acceptable run times. Using an uncoated, fused-silica capillary (internal diameter 50 microm, total length 48.5 cm, effective length 40.0 cm) and a background electrolyte consisting of a pH 3.0, 100 mM phosphate buffer containing 1.25 mM cyclodextrin, reboxetine enantiomers were baseline separated (resolution > 4) with a voltage of 20 kV in less than 16 min. Since pure enantiomers of reboxetine were not available, they were obtained from the racemic powder by means of direct-phase, high-performance liquid chromatography and their identity confirmed by circular dichroism spectra.

show abstract

Pharmacokinetics of reboxetine enantiomers in the dog

Cited by 15 publications

References 3 publications

Hemodynamic effects of reboxetine in healthy male volunteers*

Hemodynamic effects of reboxetine in healthy male volunteers*

Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs

Separation of reboxetine enantiomers by means of capillary electrophoresis

Contact Info

Product

Resources

About