The determination of essential clearance, volume, and residence time parameters of recirculating metabolic systems: The reversible metabolism of methylprednisolone and methylprednisone in rabbits

Abstract

Methods based on moment analysis are described which permit the calculation of the fundamental parameters of reversible drug/metabolite systems. These parameters include the four essential clearances of reversible and irreversible elimination, the central and steady-state distributional volumes, and the sojourn times or turnover rates of the metabolic pair. Additional parameters unique to interconversion systems are developed which describe the properties of metabolic entrapment ("recycled fraction"), conservation ("exposure enhancement"), and equilibrium resulting from reversible metabolism ("Percent parent drug at steady-state"). Parameters obtained by these methods are compared to those generated by conventional mammillary analysis. The influence of perturbation of essential parameters on the response of mammillary descriptors and the state of the interconversion system are simulated. The interconversion analysis is applied to disposition data for methylprednisolone and methylprednisone in the rabbit. Mammillary methods underestimate the metabolic clearance of these two steroids by 30%, while steroid turnover is underestimated by 100%. The steady-state volumes of distribution of the two steroids are overestimated by 10 and 61%. Additional literature data for disposition of several corticosteroids in various species and disease states are reanalyzed. Examination of cortisol/cortisone disposition in thyroid disorders reveals that mammillary methods detect the overall acceleration of steroid elimination in hyperthyroidism, but fail to reveal a 50% reduction in metabolite backconversion and decreased metabolic cycling. These moment analysis methods should facilitate characterization of the pharmacokinetics of the increasing array of reversible drug/metabolite systems.

Interplay of Phase II Enzymes and Transporters in Futile Cycling: Influence of Multidrug Resistance-Associated Protein 2-Mediated Excretion of Estradiol 17β-d-Glucuronide and Its 3-Sulfate Metabolite on Net Sulfation in Perfused TR−and Wistar Rat Liver Preparations

“…Previous examples of interconversion had revealed parallel decay half-lives of drug and metabolite, and AUC relationships that allowed interconversion metabolic intrinsic clearances to be estimated (Wagner et al, 1981;Ebling and Jusko, 1986;Ferry and Wagner, 1986;Aarons, 1987;Cheng and Jusko, 1990a,b,c, 1991, 1993a. These solutions mainly pertain to flow-limited substrates and lack consideration of transporters.…”

Pharmacokinetics of reversible metabolic systems

“…A typical example of a reversible drug/metabolite system is shown in Figure 2 for methylprednisolone and methylprednisone, each given intravenously to normal rabbits . 59 The process usually engenders polyexponential curves for all compounds as the interconversion mechanism is, in effect, a two-or morecompartment system and the formed metabolite partner shows an initial formation phase. If all clearance and distribution mechanisms are linear, there will be an eventual terminal phase where plasma concentrations of all compounds decline in parallel.…”

Mechanism of the Drug Interaction Between Valproic Acid and Carbapenem Antibiotics in Monkeys and Rats

“…According to Ebling and Jusko's model (Scheme 1; Ebling and Jusko, 1986), which is applied to the pharmacokinetic study of compounds displaying interconversion reaction, the biggest difference in the pharmacokinetic parameters between coadministered rats and control rats was observed at CL 21 , the step of the hydrolysis process of VPA-G, although, some small differences were observed at CL 12 and CL 20 (Table 6). These results suggest that the most critical point on drug interaction between carbapenems and VPA is the hydrolysis process of VPA-G, which carbapenems inhibit specifically.…”

“…Their AUCs (0.23 g ⅐ h/ml for S-4661, 0.19 g ⅐ h/ml for PAPM) were significantly lower than that of control rats (1.88 g ⅐ h/ml) ( Table 5). These data were applied to the interconversion model (Scheme 1; Ebling and Jusko, 1986), and the resultant clearance parameters were shown in Table 6. VPA-G hydrolysis clearance (CL 21 ) dramatically decreased to one-sixth to one-seventh that of control after coadministration with carbapenems; however, VPA-G or PAPM to rats (30 mg/kg i.v.…”