Bioavailability of cimetidine in man

Walkenstein, Sidney S.; Dubb, Jeffrey W.; Randolph, Warren C.; Westlake, Wilfred J.; Stote, Robert M.; Intoccia, A.P.

doi:10.1016/0016-5085(78)90762-x

Cited by 158 publications

(46 citation statements)

References 9 publications

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“…As expected, the scaled passive permeability of metformin across the apical and basal membranes of Simulated mean plasma cimetidine concentrations after a single 300 mg oral dose only matched observed values from 3 h (Walkenstein et al, 1978); at earlier time points some individual profiles showed double peaks that were not recovered by the first-order absorption function ( Figure 4A). …”

Section: Initial Modelsupporting

confidence: 63%

“…A C C E P T E D M A N U S C R I P T (Grahnen et al, 1979;Lebert et al, 1981;Somogyi and Gugler, 1985;Villeneuve et al, 1983;Walkenstein et al, 1978) Retrograde calculation A C C E P T E D M A N U S C R I P T…”

Section: Model Full Pbpkmentioning

confidence: 98%

“…For metformin, its kinetics after single 500-1500 mg oral doses and 500 mg BID oral doses was simulated (Balan et al, 2001;Gusler et al, 2001;Karttunen et al, 1983;Pentikainen, 1986;Scheen et al, 1994;Tucker et al, 1981;Tzvetkov et al, 2009). For cimetidine, its kinetics after single 300 mg oral doses and multiple 400mg BID and TID oral doses was simulated (Kirch et al, 1989;Muirhead et al, 1986;Somogyi et al, 1987;Walkenstein et al, 1978).…”

Section: Model Verificationmentioning

confidence: 99%

“…Total metabolic clearance in the liver was incorporated in the model by back-calculation of intrinsic metabolic clearance from total blood clearance following an intravenous dose (41.0 L/h) after subtraction of renal clearance with respect to blood (32.6 L/h), using the retrograde calculation method described by Jamei et al 2014 (Grahnen et al, 1979;Jamei et al, 2014;Lebert et al, 1981;Somogyi and Gugler, 1985;Villeneuve et al, 1983;Walkenstein et al, 1978).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

Burt

Neuhoff

Almond

et al. 2016

European Journal of Pharmaceutical Sciences

100

131

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Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500-fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8-18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflux.

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Section: Initial Modelsupporting

confidence: 63%

Section: Model Full Pbpkmentioning

confidence: 98%

Section: Model Verificationmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

See 2 more Smart Citations

Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug–drug interactions

Burt

Neuhoff

Almond

et al. 2016

European Journal of Pharmaceutical Sciences

100

131

View full text Add to dashboard Cite

show abstract

“…Several authors have considered this type of model, particulary Pedersen (5) who, basing his work on Walkenstein's study of cimetidine (6), suggested a bicompartmental model with a delay in reabsorption. Steimer (7) modified Harrison and Gibaldi's model (8) by introducing a delay time between the two compartments.…”

Section: Introductionmentioning

confidence: 99%