Primary, secondary, and tertiary metabolite kinetics

Abstract

Because of the propensity of nascently formed metabolites towards sequential metabolism within formation organs, theoretical and experimental treatments that achieve mass conservation must recognize the various sources contributing to primary, secondary, and tertiary metabolite formation. A simple one-compartment open model, with first-order conditions and the liver as the only organ of drug disappearance and metabolite formation, was used to illustrate the metabolism of a drug to its primary, secondary, and tertiary metabolites, encompassing the cascading effects of sequential metabolism. The concentration-time profiles of the drug and metabolites were examined for two routes of drug administration, oral and intravenous. Formation of the primary metabolite from drug in the gut lumen, with or without further absorption, and metabolite formation arising from first-pass metabolism of the drug and the primary metabolite during oral absorption were considered. Mass balance equations, incorporating modifications of the various absorption and conversion rate constants, were integrated to provide the explicit solutions. Simulations, with and without consideration of the sources of metabolite formation other than from its immediate precursor, were used to illustrate the expected differences in circulating metabolite concentrations. However, a simple relationship between the area under the curve of any metabolite, M, or [AUC (m)], its clearance [CL(m)], and route of drug administration was found. The drug dose, route, fraction absorbed into the portal circulation, Fabs, fraction available of drug from the liver, F, availabilities of the metabolites F(m) from formation organs, and CL(m) are determinants of the AUC(m)'s. After iv drug dosing, the area of any intermediary metabolites is determined by the iv drug dose divided by the (CL(m)/F(m] of that metabolite. When a terminal metabolite is not metabolized, its area under the curve becomes the iv dose of drug divided by the clearance of the terminal metabolite since the available fraction for this metabolite is unity. Similarly, after oral drug administration, when loss of drug in the gut lumen does not contribute to the appearance of metabolites systematically, the general solution for AUC(m) is the product of Fabs and oral drug dose divided by [CL(m)/F(m)]. A comparison of the area ratios of any metabolite after po and iv drug dosing, therefore, furnishes Fabs. When this fraction is divided into the overall systemic availability or Fsys, the drug availability from the first-pass organs, F, may be found.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics and metabolism of diltiazem in rabbits after a single intravenous or single oral administration

“…However, quantitatively, the concentrations of the metabolites tended to be higher after the intravenous dose, although only the data for Ml reached statistical significance (Table I, P < 0.05). Assuming the kinetics are linear, if the AUC of the metabolites were truly higher after the intravenous route, it may imply that DTZ was not completely absorbed after the oral dose and/or that the clearance of DTZ and its metabolites was higher during the first pass through the liver (i.e., a higher sequential first pass effect of DTZ) (20). Higher clearances of the metabolites after the oral dose would unlikely be attributable to increased urinary excretion since the renal clearances of the metabolites showed a tendency to be higher after the intravenous dose.…”

Formed and preformed metabolites: facts and comparisons

“…Second, for mass balance considerations, the sequential removal of P to Mi then Mii reduces the appearance of Mi by the factor E{mi,P}, and directly yields Mii. Thus, there are two sources for Mii formation: one from Mi that is circulating (represented by the metabolic rate constant for Mi, k m {mi}, and one from P that is sequentially being metabolized to Mii (represented by k mi E{mi,P}) ( Figure 2B) (St-Pierre et al 1988). For the simplest one-compartment model, the circulating levels of the metabolite may be related to the formation rate constant from precursor as normally considered, except that the F{mi,P} term should also be present ( Figure 2C).…”

The Use of In Vitro Data and Physiologically-Based Pharmacokinetic Modeling to Predict Drug Metabolite Exposure: Desipramine Exposure in Cytochrome P4502D6 Extensive and Poor Metabolizers Following Administration of Imipramine

“…The establishment of drug metabolite kinetic principles dates back to the 1980s (Houston, 1981;Houston and Taylor, 1984;Pang, 1985;St-Pierre et al, 1988). However, although the use of in vitro studies to predict in vivo pharmacokinetics of drugs is commonplace, the use of these approaches to predict pharmacokinetics of metabolites has not been thoroughly established due to the number of contributing variables on metabolite exposure.…”