Enantioselective tissue distribution of the basic drugs disopyramide, flecainide and verapamil in rats: role of plasma protein and tissue phosphatidylserine binding. 1998

K Hanada, and S Akimoto, and K Mitsui, and K Mihara, and H Ogata
Department of Biopharmaceutics, Meiji College of Pharmacy, Tokyo, Japan.

OBJECTIVE The stereoselective distribution of three basic drugs, disopyramide (DP), flecainide (FLC) and verapamil (VP), was studied to clarify the relationship between the tissue-to-unbound plasma concentration ratio (Kpf) and drug lipophilicity and binding to phosphatidylserine phs), which are possible factors determining the tissue distribution of these drug enantiomers. METHODS The drug enantiomer or racemate was administered to rats by intravenous constant infusion. Their concentrations in plasma and tissues were determined using enantioselective high-performance liquid chromatography. Plasma protein binding, and buffer-octanol and buffer-hexane containing PhS partition coefficients were also determined. RESULTS The stereoselectivity of the tissue-to-plasma concentration ratio (Kp) was partly associated with that of serum protein binding. However, the Kpf value of R(+)-VP in the lung was significantly higher than that of S(-)-VP. A linear correlation was observed between the Kpf values of these drug enantiomers in brain, heart, lung and muscle, and their buffer-hexane containing PhS partition coefficients. The in vitro data for the binding of these drugs to PhS suggest that stereoselective binding of VP to PhS may correspond to its stereoselective tissue binding. CONCLUSIONS Our findings provide some evidence for a role of tissue PhS in the tissue distribution of basic drugs with respect to stereoselectivity of drug enantiomers distribution.

UI MeSH Term Description Entries
D008297 Male Males
D010718 Phosphatidylserines Derivatives of PHOSPHATIDIC ACIDS in which the phosphoric acid is bound in ester linkage to a SERINE moiety. Serine Phosphoglycerides,Phosphatidyl Serine,Phosphatidyl Serines,Phosphatidylserine,Phosphoglycerides, Serine,Serine, Phosphatidyl,Serines, Phosphatidyl
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D001798 Blood Proteins Proteins that are present in blood serum, including SERUM ALBUMIN; BLOOD COAGULATION FACTORS; and many other types of proteins. Blood Protein,Plasma Protein,Plasma Proteins,Serum Protein,Serum Proteins,Protein, Blood,Protein, Plasma,Protein, Serum,Proteins, Blood,Proteins, Plasma,Proteins, Serum
D004206 Disopyramide A class I anti-arrhythmic agent (one that interferes directly with the depolarization of the cardiac membrane and thus serves as a membrane-stabilizing agent) with a depressant action on the heart similar to that of guanidine. It also possesses some anticholinergic and local anesthetic properties. Diisopyramide,Disopyramide Monohydrochloride,Disopyramide Phosphate,Disopyramide Phosphate (1:1),Disopyramide Phosphate (1:1), (+-)-Isomer,Disopyramide Phosphate (1:1), (R)-Isomer,Disopyramide Phosphate (1:1), (S)-Isomer,Disopyramide, (+-)-Isomer,Disopyramide, (R)-Isomer,Disopyramide, (S)-Isomer,Disopyramide, D-Tartrate (1:1), (S)-Isomer,Disopyramide, L-Tartrate (1:1), (R)-Isomer,Disopyramide, L-Tartrate (1:1), (S)-Isomer,Disopyramide, L-Tartrate (1:2), (+-)-Isomer,Disopyramide, L-Tartrate, (S)-isomer,Norpace,Palpitin,Palpitine,Rhythmodan,Ritmilen,Rythmilen,SC-13957,SC 13957,SC13957
D005424 Flecainide A potent anti-arrhythmia agent, effective in a wide range of ventricular and atrial ARRHYTHMIAS and TACHYCARDIAS. Flecainide Acetate,Apocard,Flecadura,Flecainid-Isis,Flecainide Monoacetate,Flecainide Monoacetate, (+-)-Isomer,Flecainide Monoacetate, (R)-Isomer,Flecainide Monoacetate, (S)-Isomer,Flecainide, (R)-Isomer,Flecainide, (S)-Isomer,Flecainide, 5-HO-N-(6-oxo)-Derivative,Flecainide, 5-HO-N-(6-oxo)-Derivative, (+-)-Isomer,Flecatab,Flécaïne,R818,Tambocor,Flecainid Isis
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000889 Anti-Arrhythmia Agents Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. Anti-Arrhythmia Agent,Anti-Arrhythmia Drug,Anti-Arrhythmic,Antiarrhythmia Agent,Antiarrhythmia Drug,Antiarrhythmic Drug,Antifibrillatory Agent,Antifibrillatory Agents,Cardiac Depressant,Cardiac Depressants,Myocardial Depressant,Myocardial Depressants,Anti-Arrhythmia Drugs,Anti-Arrhythmics,Antiarrhythmia Agents,Antiarrhythmia Drugs,Antiarrhythmic Drugs,Agent, Anti-Arrhythmia,Agent, Antiarrhythmia,Agent, Antifibrillatory,Agents, Anti-Arrhythmia,Agents, Antiarrhythmia,Agents, Antifibrillatory,Anti Arrhythmia Agent,Anti Arrhythmia Agents,Anti Arrhythmia Drug,Anti Arrhythmia Drugs,Anti Arrhythmic,Anti Arrhythmics,Depressant, Cardiac,Depressant, Myocardial,Depressants, Cardiac,Depressants, Myocardial,Drug, Anti-Arrhythmia,Drug, Antiarrhythmia,Drug, Antiarrhythmic,Drugs, Anti-Arrhythmia,Drugs, Antiarrhythmia,Drugs, Antiarrhythmic
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D014018 Tissue Distribution Accumulation of a drug or chemical substance in various organs (including those not relevant to its pharmacologic or therapeutic action). This distribution depends on the blood flow or perfusion rate of the organ, the ability of the drug to penetrate organ membranes, tissue specificity, protein binding. The distribution is usually expressed as tissue to plasma ratios. Distribution, Tissue,Distributions, Tissue,Tissue Distributions

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