The diastolic heart beat of the apical "window" in constrictive pericarditis.
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J S Barrett
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Integrated pharmacokinetic and metabolic modeling of ipriflavone and metabolites after oral administration.
PURPOSE: Disposition of ipriflavone, an agent indicated for the treatment of osteoporosis, is highly variable after oral administration. Ipriflavone has five major metabolites (M1, M2, M3, M4, and M5). The metabolites M2 and M5 have activity and are major metabolic constituents in humans. Hence, it is important to characterize both ipriflavone and metabolites simultaneously. Our purpose was to develop an integrated pharmacokinetic/metabolic model that simultaneously predicts plasma concentrations of ipriflavone and metabolites after a single oral administration. METHOD: The model was based on the reported metabolic conversion of ipriflavone to M1, M3, and M4; subsequent conversion of M4 to M5; and conversion of both M1 and M3 to M2 in rats. The further conversion of M5 to M6 and M7 was ignored, as this conversion represents an insignificant portion of the total metabolite pool. The input function was described by a first-order constant. Each analyte required two-compartment disposition. The elimination/nonmetabolic constants for each analyte accounted for urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which 16 healthy male volunteers were administered 200 mg of an ipriflavone corn suspension were used to examine the predictability of this model. RESULTS: The coefficient of determination was 0.99, and model selection criterion was 3.7 for mean data fits supporting the goodness-of-fit and predictability of the model. The model also predicted negligible urinary recoveries for ipriflavone, M1, M3, and M4; M2 and M5 had high urinary recoveries. The metabolic conversion constant from M3 to M2 was negligible. Divergence from the proposed pathway may be attributed to the species differences in metabolism between humans and rats. CONCLUSIONS: Model predictions supported the improvement in bioavailability with corn-oil suspension compared to the conventional oral tablet. Future model applications may also help identify significant covariates (i.e., age, gender, and disease state) in proposed clinical trials.
Administration, Oral↗
Pharmacokinetics of ipriflavone and metabolites after oral administration of a corn-oil suspension relative to the Osteofix tablet.
Ipriflavone (IP) is a derivative of naturally occurring isoflavones and is marketed as Osteofix for the treatment of osteoporosis in Europe. IP has poor aqueous solubility, and the Osteofix compressed tablet has poor and variable bioavailability (F ). IP is incompletely absorbed after oral administration and is converted to five major metabolites (M1, M2, M3, M4, and M5). It is also further converted to metabolites M6 and M7 to a very small extent. The metabolites, especially M2 and M5, also have activity. A pilot study was conducted in healthy male volunteers that showed an 8- to 20-fold increase in the IP bioavailability after administration of Osteofix tablets in the fed state relative to the fasting state. A four-way crossover study was conducted in 16 healthy male volunteers, receiving Osteofix in fed state and 50, 100, and 200 mg of IP corn-oil suspension in fasted state. All IP administrations were safe and well tolerated. There was a reduction in the IP plasma level variability after 100-mg corn-oil administration as compared with that for the tablet. There was an increased relative F after the suspension, which was such that the 50-mg IP corn-oil suspension yielded similar levels as the 200-mg tablet. M5 was the major metabolite, consistent with earlier reports. The area under the curve to the last measured time point (AUC ( t ) ) levels were lower for M5, M3, and M2; higher for M1 and M2; and similar for IP after 50-mg corn-oil administration, as compared with the values for the tablet. This result may partially be explained by differences in the half-lives. Absorption/formation of M2 was delayed. The metabolite formation, except for M1 and M5, decreased with increased doses, which was accompanied by the prolonged half-life of IP and nonproportional increase in the IP AUC ( t ). This result may be due to autoinhibition of IP metabolism, because IP is an inhibitor of CYP3A4, and the metabolism of IP may be partly CYP3A4 mediated. Osteofix F may be improved by formulations that increase solubility, such as the corn-oil suspension. Although equivalent IP exposure from the tablet may be achieved at much lower overall doses because of the improved F by the corn-oil suspension, higher doses may require reconfirmation of safety and efficacy, given the differences in metabolic profiles obtained at higher doses.
Administration, Oral↗