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Influence of Stereoselective Pharmacokinetics in the Development and Predictability of an IVIVC for the Enantiomers of Metoprolol Tartrate

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Abstract

Purpose. To investigate the ability of an IVIVC developedwith a racemate drug as well as each enantiomer in predicting the invivo enantiomer drug performance.

Methods. Dissolution of metoprolol extended releasetablets with different release characteristics (e.g., fast (F),moderate (M), and slow (S)) was performed using USP ApparatusI, pH 1.2, 50 rpm. Metoprolol racemate tablets (S, M, and F, 100 mg) and 50mg oral solution were administered to healthy volunteers, blood samples werecollected over 24 (solution) and 48 (tablet) hours and assayed. IVIVC modelsdeveloped were: (1) Racemate-fraction of drug dissolved (FRD) vsRacemate-fraction of drug absorbed (FRA), (2) R-FRD vs R-FRA, and (3) S-FRDvs S-FRA for combinations of formulations (S/M/F, S/M, S/F, and M/F).Enantiomer Cmax and AUC prediction errors (PEs) were estimated for modelevaluation after convolution of in vivo release rates.

Results. The R-IVIVC and S-IVIVC accurately predicted theR- and S-metoprolol pharmacokinetic profiles, respectively. The averagedprediciton errors (PE) for the enantiomer Cmax and AUC were less than10% for S/M/F, M/F, and S/F IVIVC models. Racemate-IVIVC (M/F) wasable to predict S-enantiomer with an average %PE of 2.52 for S-Cmaxand 4.3 for S-AUC. However, the racemate-IVIVC was unable to predict theR-enantiomer pharmacokinetic profile.

Conclusions. Metoprolol racemate data cannot be used toaccurately predict R-enantiomer drug concentrations. However, the racematedata was predictive of the active stereoisomer.

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Authors and Affiliations

  1. Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 100 Penn Street, AHB, Baltimore, Maryland, 21201-6808

    Nattee Sirisuth

  2. Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 100 Penn Street, AHB, Baltimore, Maryland, 21201-6808

    Natalie D. Eddington

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  1. Nattee Sirisuth
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  2. Natalie D. Eddington
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Sirisuth, N., Eddington, N.D. Influence of Stereoselective Pharmacokinetics in the Development and Predictability of an IVIVC for the Enantiomers of Metoprolol Tartrate. Pharm Res 17, 1019–1025 (2000). https://doi.org/10.1023/A:1007595725360

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