Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride.
The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [¹⁴C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (∼240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (∼679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (∼31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (∼19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (∼17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed.
Forest Research Institute, Farmingdale, NY, USA.
Fanying
F
Li
Christina
C
Chin
Julie
J
Wangsa
John
J
Ho
D000284:Administration, Oral; D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D000078764:Milnacipran; D008954:Models, Biological; D015394:Molecular Structure; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D018759:Adrenergic Uptake Inhibitors; D002250:Carbon Radioisotopes; D003521:Cyclopropanes; D020719:Glucuronides; D000078764:Milnacipran; D017367:Selective Serotonin Reuptake Inhibitors