Fractions metabolized in a triangular metabolic system: Cinromide and two metabolites in the rhesus monkey

Lane, Elizabeth A.

doi:10.1007/bf01061475

Cited by 6 publications

(1 citation statement)

References 13 publications

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“…Therefore, further studies are needed to address unambiguously the disposition of the metabolites of BMY-21502. In this context, the study design previously put forward, for a triangular metabolic system (20), needs to be explored to assess the fraction of the parent drug, BMY-21502, metabolized to BMY-42191 and BMY-40440.…”

Section: Inspection Ofmentioning

confidence: 99%

Pharmacokinetics of a nootropic agent, BMY-21502, and its metabolites in beagle dogs

Srinivas

Kaul

1998

European Journal of Drug Metabolism and Pharmacokinetics

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A preliminary investigation into the pharmacokinetics of BMY-21502, a nootropic agent, and two of its metabolites, BMY-42191 and BMY-40440, was performed in 4 beagle dogs. Following oral dosing of a solution of BMY-21502 (0.61 mmoles), plasma samples were obtained for 24 h and analyzed for the three analytes by a validated HPLC assay. BMY-21502 was rapidly absorbed (Tmax = 0.5 +/- 0.3 h), followed by a rapid decline of the plasma levels (T1/2 = 0.95 +/- 0.1 h). The hydroxy metabolite, BMY-42191, was rapidly formed and the peak concentrations in plasma were obtained by 2.88 +/- 0.2 h. On the contrary, there was a considerable delay in the peaking of the ketone metabolite, BMY-40440 (Tmax = 6 h). The T1/2 values for BMY-40440 (5.58 +/- 0.5 h) were longer than those for BMY-42191 (4.28 +/- 1.2 h). Comparison of AUC values for BMY-42191 (326.43 +/- 63.3 h x microM) with those of BMY-40440 (67.52 +/- 8.4 h x microM) or BMY-21502 (69.35 +/- 7.3 h x microM) indicated that BMY-42191 was the major circulating species in dog plasma. In conclusion, the preliminary data indicate that the metabolism of BMY-21502 is complex and may encompass hydroxy-ketone metabolic interconversions, as reported for other xenobiotics.

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Section: Inspection Ofmentioning

confidence: 99%

Pharmacokinetics of a nootropic agent, BMY-21502, and its metabolites in beagle dogs

Srinivas

Kaul

1998

European Journal of Drug Metabolism and Pharmacokinetics

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Primary, secondary, and tertiary metabolite kinetics

St‐Pierre

Pang

1988

Journal of Pharmacokinetics and Biopharmaceutics

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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)

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Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs

Sintov

Bialer

Yagen

1988

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Fractions metabolized in a triangular metabolic system: Cinromide and two metabolites in the rhesus monkey

Cited by 6 publications

References 13 publications

Pharmacokinetics of a nootropic agent, BMY-21502, and its metabolites in beagle dogs

Pharmacokinetics of a nootropic agent, BMY-21502, and its metabolites in beagle dogs

Primary, secondary, and tertiary metabolite kinetics

Pharmacokinetics and protein binding of trichothecene mycotoxins, T-2 toxin and HT-2 toxin, in dogs

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