{'fraction_non_alphanumeric': 0.038130381303813035, 'fraction_numerical': 0.014145141451414513, 'mean_word_length': 4.749116607773852, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Disposition of methylprednisolone and its sodium succinate prodrug in vivo and in perfused liver of rats: nonlinear and sequential first-pass elimination.

The disposition of methylprednisolone (MP) and its prodrug succinate ester, methylprednisolone sodium succinate (MS), were examined both in vivo and in situ (perfused livers) in rats. In vivo studies included iv and oral dosing of 10 or 50 mg/kg of MP in both forms, while liver perfusion involved initial perfusate concentrations of 5 and 25 micrograms/mL of either compound. Steroid concentrations were measured by HPLC. In the intact rat, clearance (CL) values of both compounds were high, twice the hepatic plasma flow, and decreased by one-half after the high dose, indicating nonlinear kinetics. The volumes of distribution of MS and MP were essentially constant with dose. Incomplete availability of MP from iv MS (52-55%) and from the oral dose (10%) was found. Sequential first-pass metabolism was investigated in situ. Extensive hepatic extraction of MP (84%) occurred at the low dose, but decreased to 48% at the high dose, supporting in vivo observations of high CL and nonlinearity. Extraction of MS was also high (83%), but MP availability was slight (8%). The MS and MP data were fitted to a sequential first-pass model yielding an average fraction of MS metabolized-to-MP value of 0.22. The prodrug MS and the active metabolite MP thus demonstrate both systemic and hepatic nonlinearity in rats, and the low availability of MP from iv MS was due, in part, to sequential first-pass elimination. This factor is more extensive in rats than in other species.