Theoretical decrease in systemic availability with decrease in input rate at steady‐state for first‐pass drugs

An aqueous solution containing 1 mg of adinazolam mesylate per ml was administered orally as a single dose (40 mg) and with loading doses followed by hourly doses such that final dose rates of 1, 2, and 3 mg h-1 were administered to steady-state. Four subjects exhibited linear steady-state kinetics, while the other four exhibited Michaelis-Menten kinetics, based on measurement by HPLC of both unchanged drug and the major N-demethyl metabolite. The drug is very rapidly absorbed and has an intrinsic clearance of total (bound + free) drug which averaged 2.14 l min-1 based on the steady-state data and 1.17 l min-1 based on the single dose data, but these means do not differ significantly. The apparent metabolite clearance, CLmc/fm (where fm = fraction of adinazolam converted to the N-demethyl metabolite), averaged 0.170 l min-1 based on steady-state data and 0.179 l min-1 based on single dose data and these means do not differ significantly. Pharmacokinetic parameters, such as these clearances, had large intersubject variations. Three types of bioavailabilities were estimated from the data.

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Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man

Wagner

Rogge

Natale

et al. 1987

Biopharm & Drug Disp

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A computer simulation of the food effect: Transient changes in hepatic blood flow and michaelis‐menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol

Semple

Tam

Coutts

1990

Biopharm & Drug Disp

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A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis-Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal. The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg-1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.

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Propranolol Elimination as Described by the Venous Equilibrium Model Using Flow Perturbations in the Isolated Perfused Rat Liver

Smallwood¹,

Mihaly

Smallwood

et al. 1988

Journal of Pharmaceutical Sciences

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Theoretical decrease in systemic availability with decrease in input rate at steady‐state for first‐pass drugs

Cited by 9 publications

References 6 publications

Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man

Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man

A computer simulation of the food effect: Transient changes in hepatic blood flow and michaelis‐menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol

Propranolol Elimination as Described by the Venous Equilibrium Model Using Flow Perturbations in the Isolated Perfused Rat Liver

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