Plasma Concentrations and Beta-Blocking Effects in Normal Volunteers After Intravenous Doses of Metoprolol and Propranolol

Regårdh, Carl-g.; Johnsson, G.; Jordö, L.; Lungborg, Per; Persson, Bengt-a.; Rönn, O.

doi:10.1097/00005344-198011000-00002

Cited by 28 publications

(15 citation statements)

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“…In 34 cases out of 36, the concentrations of metoprolol decreased sharply immediately after the end of the infusion, as illustrated in Figure 1 by an individual 10 8 4 6…”

Section: Resultsmentioning

confidence: 92%

“…36 plasma profiles of deuterated metoprolol (which was shown to have a pharmacokinetic behaviour identical to that of the non-labelled drug, see data analysis) were thus obtained. The pharmacokinetics of metoprolol after intravenous administration have already been evaluated (3)(4)(5)(6). However, the availability of so many plasma profiles gave us the opportunity to investigate the intra-individual variability and to assess the inter-subject variability of metoprolol pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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Inter- and intra-subject variability of metoprolol kinetics after intravenous administration

Richard¹,

Jm²,

Godbillon³

1994

Eur. J. Drug Metab. Pharmacokinet.

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The pharmacokinetics of metoprolol were assessed from the data of 3 experiments in which intravenous deuterated metoprolol was given concomitantly with various oral metoprolol formulations to healthy volunteers. The plasma levels after intravenous administration were well described by a biexponential equation. However, a deviation from a pure biphasic decline was observed over a short period of time, immediately after the rapid elimination phase. The inter- and intra-subject variability of the parameters describing the two-compartment model was large. The intra-subject variability of the terminal half-life and the plasma clearance was lower than their inter-subject variability. The plasma clearance was linearly related to 1/t1/2. Contrarily to the other parameters of the model, t1/2 appeared to be a characteristic of the subject.

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“…In 34 cases out of 36, the concentrations of metoprolol decreased sharply immediately after the end of the infusion, as illustrated in Figure 1 by an individual 10 8 4 6…”

Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Inter- and intra-subject variability of metoprolol kinetics after intravenous administration

Richard¹,

Jm²,

Godbillon³

1994

Eur. J. Drug Metab. Pharmacokinet.

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“…The in vivo PK data obtained from literature and used in the current simulations include Cp-time profiles after i.v. infusion administration (42,43), jejunal and colonic perfusion (44), p.o. administration of IR formulations (45,46), and p.o.…”

Section: Metoprololmentioning

confidence: 99%

“…The accuracy of prediction of metoprolol distribution and pharmacokinetics using the PBPK model was verified in simulations of i.v. doses (42,43). The same PBPK model was then used to simulate jejunal and colonic perfusion studies.…”

Section: Metoprololmentioning

confidence: 99%

“…In the new equation, the contribution of the binding of neutral and anionic forms of molecules to tissue albumin and the contribution of the cationic form of molecules to tissue acidic phospholipids are directly related to the molecule's ionization state in plasma at pH=7.4. The volume of distribution calculated using the tissue volumes and in silico K p values was 275 L. The total volumes of distribution fitted to available sets of intravenous data (42)(43)(44)63) ranged from 200 to 535 L. The metabolic clearance of metoprolol was predicted by scaling in vitro measured K m and V max values to in vivo conditions assuming 38 mg of values were 9% and 6% after i.v. and p.o.…”

Section: Metoprololmentioning

confidence: 99%

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Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Lukáčová

Woltosz

Bolger

2009

AAPS J

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Abstract. The aim of this study was to demonstrate the value of mechanistic simulations in gaining insight into the behaviors of modified release (MR) formulations in vivo and to use the properly calibrated models for prediction of pharmacokinetics (PK) and pharmacodynamics (PD). GastroPlus TM (Simulations Plus, Inc.) was used to fit mechanistic models for adinazolam and metoprolol that describe the absorption, PK, and PD after intravenous (i.v.) and immediate release (IR) oral (p.o.) administration. The fitted model for adinazolam was then used to predict the PD profile for a MR formulation and to design a new formulation with desired onset and duration of action. The fitted metoprolol model was used to gain insight and to explain the in vivo behaviors of MR formulations. For each drug, a single absorption/PK model was fitted that provided simulated plasma concentration-time profiles closely matching observed in vivo profiles across several different i.v. and p.o doses. Sedation score profiles of adinazolam were fitted with an indirect PD model. For metoprolol, the fitted absorption/ PK model for IR p.o. doses was used to select in vitro dissolution conditions that best matched the in vivo release of MR doses. This model also explained differences in exposure after administration of MR formulations with different release rates. Mechanistic absorption/PK models allow for detailed descriptions of all processes affecting the two drugs' bioavailability, including release/dissolution, absorption, and intestinal and hepatic first pass extraction. The insights gained can be used to design formulations that more effectively overcome identified problems.

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Biliary excretion and enterohepatic circulation of two beta‐adrenergic blocking drugs, exaprolol and propranolol in rats

Tomcíková

Bezek

Ďurišová

et al. 1984

Biopharm & Drug Disp

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Plasma levels and excretion of two beta-adrenoceptor blocking drugs 3H-exaprolol and 3H-propranolol were observed up to 96 h after a single i.v. administration to rats. Terminal half-lives of 26.8 +/- 9.1 h and 51.3 +/- 7.5 h were found for exaprolol and propranolol, respectively. The recovery of 3H radioactivity in feces following i.v. administration of the drugs (34.2 +/- 0.8 per cent and 12.0 +/- 1.3 per cent 3H of exaprolol and propranolol, respectively) is of biliary origin, as 30.7 +/- 3.5 per cent and 13.4 +/- 3.6 per cent 3H of exaprolol and propranolol, respectively, was excreted in the bile after i.v. administration. Enterohepatic circulation of the drugs was studied using the donor-recipient rat method. After intraduodenal administration of donor bile to the recipient rat approximately 50 per cent and 40 per cent of the biliary 3H activity of exaprolol and propranolol, respectively, was re-excreted following absorption. A formula for calculating the amount of the substance together with its metabolites excreted in the bile, urine or feces as a result of enterohepatic circulation has been proposed.

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Plasma Concentrations and Beta-Blocking Effects in Normal Volunteers After Intravenous Doses of Metoprolol and Propranolol

Cited by 28 publications

References 0 publications

Inter- and intra-subject variability of metoprolol kinetics after intravenous administration

Inter- and intra-subject variability of metoprolol kinetics after intravenous administration

Prediction of Modified Release Pharmacokinetics and Pharmacodynamics from In Vitro, Immediate Release, and Intravenous Data

Biliary excretion and enterohepatic circulation of two beta‐adrenergic blocking drugs, exaprolol and propranolol in rats

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