Urinary profile of methylprednisolone acetate metabolites in patients following intra-articular and intramuscular administration

Abstract

A study on urinary metabolites of methylprednisolone acetate (MPA) has been performed by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) in precursor ion scanning (PIS) and neutral loss (NL) modes. Patients suffering from joint inflammation have been treated with Depo-Medrol® (MPA marketed suspension, 40 mg) intra-articularly (IA) and after a wash-out period, intramuscularly (IM) at the same dose. Urine samples have been collected after both the administration routes. Metabolites were identified in PIS mode by setting the fragment ion at m/z 161 which is specific for MPA, methylprednisolone (MP), methylprednisolone hemisuccinate, and in NL mode by selecting the losses of 54, 72, 176 and 194 Da. The MP-related structure of each target ion detected in both the MS modes was then confirmed by MS/MS acquisitions, and by accurate mass experiments. By using this approach, 13 MPA metabolites (M1-M13) have been identified, nine already reported in the literature and four unknown and for which the chemical structures have been proposed. No differences in the metabolic pattern of MPA when administered IM or IA were observed. The relative abundances of metabolites compared with the internal standard (MP-D2) were monitored by multiple reaction monitoring analysis for 19 days after both the administration routes.

Using complementary mass spectrometric approaches for the determination of methylprednisolone metabolites in human urine

“…M5 and M6 have not been reported after intra‐articular or intramuscular administrationor after intravenous high‐dose pulse for MP.…”

“…Thus, the most likely structure for M4 is 11β,17α,21‐trihydroxy‐6‐methylpregna‐1,4,6‐triene‐3,20‐dione. Although 6,7‐dehydration is not considered a major steroid metabolic biotransformation, several 6,7‐dehydro metabolites have been recently reported for some steroids, but they have not been reported for MP after intra‐articular or intramuscular administration or after an intravenous high‐dose pulse …”

“…A different study, based on liquid chromatography/tandem mass spectrometry (LC/MS/MS) and nuclear magnetic resonance (NMR), concluded that the metabolic pathway of MP after intravenous administration was simple: reduction of the C20 carbonyl group, further oxidation of the C20‐C21 side chain, and C6 oxidation . In a recent study performed by LC/MS/MS, metabolites detected after intramuscular and intra‐articular administrations were described . Metabolites obtained after 11‐oxidation, reduction of C20 and oxidation of the C20‐C21 side chain were also detected.…”

Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate

“…[10][11][12][13][14] The MS 1 and MS 2 spectra used to identify methylprednisolone are depicted in Figure 1. Both impurities were previously observed in a pilot methylprednisolone sodium succinate forced-degradation experiment.…”

Synthesis, purification, and chemical characterization of 20‐dihydro‐6‐methylprednisone, an isomeric metabolite of methylprednisolone in the horse, for use as an analytical standard

“…[2,3] As such, methylprednisolone is widely used on horses in training, usually as the long-acting Depo-medrol formulation administered by intra-articular or intra-muscular injection. [5][6][7][8][9] Of these metabolites, at least three isobaric compounds have been identified in rat urine [6] and four in human urine. For example, the RMTC lists methylprednisolone as a 'controlled therapeutic medication' and sets forth that a 100 pg/mL methylprednisolone threshold in plasma or serum corresponds to a seven-day 'restricted administration time' (withdrawal time) following intra-articular administration of a '100 mg total in one intra-articular space'.…”