An improved method for the determination of distribution coefficients

Stopher, D. A.; McClean, Siobhán

doi:10.1111/j.2042-7158.1990.tb05373.x

Cited by 54 publications

(53 citation statements)

References 7 publications

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“…The guidelines about log D 7.4 values and their implication for drug development are illustrated in Table 1 (Comer, 2003;Taylor and Triggle, 2007). There are many different approaches which can be used to determine a partition coefficient experimentally (Avdeef, 1993;Donovan and Pescatore, 2002;Gulyaeva et al, 2008;Hitzel et al, n.d.;Kaliszan et al, 2002;Pallicer et al, 2012Pallicer et al, , 2010Ràfols et al, 2012;Stopher and Mcclean, 1990;Takács-Novák and Avdeef, 1996;Valko et al, 2001;Wiczling et al, 2008), but the most direct one is the shake-flask method. In this method, an aqueous solution of a compound is mixed in a flask with an organic solvent (usually water saturated n-octanol).…”

Section: Introductionmentioning

confidence: 98%

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts

Andrés

Rosés

Ràfols

et al. 2015

European Journal of Pharmaceutical Sciences

163

102

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Several procedures based on the shake-flask method and designed to require a minimum amount of drug for octanol-water partition coefficient determination have been established and developed. The procedures have been validated by a 28 substance set with a lipophilicity range from -2.0 to 4.5 (logD7.4). The experimental partition is carried out using aqueous phases buffered with phosphate (pH 7.4) and n-octanol saturated with buffered water and the analysis is performed by liquid chromatography. In order to have accurate results, four procedures and eight different ratios between phase volumes are proposed. Each procedure has been designed and optimized (for partition ratios) for a specific range of drug lipophilicity (low, regular and high lipophilicity) and solubility (high and low aqueous solubility). The procedures have been developed to minimize the measurement in the octanolic phase. Experimental logD7.4 values obtained from different procedures and partition ratios show a standard deviation lower than 0.3 and there is a nice agreement when these values are compared with the reference literature ones.

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Section: Introductionmentioning

confidence: 98%

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts

Andrés

Rosés

Ràfols

et al. 2015

European Journal of Pharmaceutical Sciences

163

102

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“…where Conc initial is the concentration of compound in the initial aqueous solution, Conc final is the concentration of compound in the final aqueous phase, V aq is the volume of aqueous solution, and V oct is the volume of octanol (Stopher and McClean, 1990). Caco-2 Assay.…”

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confidence: 99%

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

et al. 2013

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Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC 50 , k inact , and K I values were 10.4 6 1.4 mM, 0.060 6 0.002 min 21 , and 1.13 6 0.12 mM for PRN, and 7.1 6 0.6 mM, 0.10 6 0.01 min 21 , and 1.95 6 0.31 mM for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC 50 values of 0.26 6 0.01 mM and 0.22 6 0.03 mM for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with k inact and K I values of 0.050 6 0.002 min 21 and 0.40 6 0.06 mM, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71-and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24-and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN.

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“…Log D was measured by a fully automated shake flask method that determines the partition of compound between octanol and phosphate buffer, pH 7.4 (Stopher and McClean, 1990). The pK a of UK-390957 was determined according to the methods described by Gobry et al (2000).…”

Section: Methodsmentioning

confidence: 99%

Measurement of Binding of Basic Drugs to Acidic Phospholipids Using Surface Plasmon Resonance and Incorporation of the Data into Mechanistic Tissue Composition Equations to Predict Steady-State Volume of Distribution

Small

Gardner²,

Jones³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Acidic phospholipid binding plays an important role in determining the tissue distribution of basic drugs. This article describes the use of surface plasmon resonance to measure binding affinity (K D ) of three basic drugs to phosphatidylserine, a major tissue acidic phospholipid. The data are incorporated into mechanistic tissue composition equations to allow prediction of the steady-state volume of distribution (V ss ). The prediction accuracy of V ss using this approach is compared with the original methodology described by Rodgers et al. (J Pharm Sci 94:1259-1276), in which the binding to acidic phospholipids is calculated from the blood/plasma concentration ratio (BPR). The compounds used in this study [amlodipine, propranolol, and 3-dimethylaminomethyl-4-(4-methylsulfanylphenoxy)-benzenesulfonamide (UK-390957)] showed higher affinity binding to phosphatidylserine than to phosphatidylcholine. When the binding affinity to phosphatidylserine was incorporated into mechanistic tissue composition equations, the V ss was more accurately predicted for all three compounds by using the surface plasmon resonance measurement than by using the BPR to estimate acidic phospholipid binding affinity. The difference was particularly marked for UK-390957, a sulfonamide that has a high BPR due to binding to carbonic anhydrase. The novel approach described in this article allows the binding affinity of drugs to an acidic phospholipid (phosphatidylserine) to be measured directly and demonstrates the utility of the binding data in the prediction of V ss . IntroductionAlong with clearance, the volume of distribution at steady state (V ss ) is a key pharmacokinetic parameter that determines how long a drug remains in the body. Several approaches have been used to prospectively predict human V ss , including scaling in vivo data from preclinical species, scaling in vitro data, and various in silico calculation methods (Obach, 2007).An approach that has gained popularity in recent years is to use in vitro and physicochemical data for a particular compound to estimate its tissue/plasma partitioning and by accounting for the volumes of different tissues and their composition. This information is used to predict V ss of a compound in an integrated physiologically based manner (eq. 1).where V is physical tissue volume, T is tissue, Kp is tissue to plasma partition coefficient, and p is plasma.Prediction of Kp on the basis of tissue composition and the physicochemical properties of a compound was first described by Poulin and Theil (2000) for neutral compounds, with emphasis on lipophilicity and binding to neutral lipids. This approach has subsequently been used by various authors to predict V ss for different compound datasets (Jones et al., 2006;De Buck et al., 2007). An extension to this mechanistic PBPK model that incorporates pH and binding of the ionized base to acidic phospholipids as an additional component of tissue binding was proposed by Rodgers et al. (2005a), initially for ionized bases. The affinity of a compound t...

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An improved method for the determination of distribution coefficients

Cited by 54 publications

References 7 publications

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts

Setup and validation of shake-flask procedures for the determination of partition coefficients (logD) from low drug amounts

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies

Measurement of Binding of Basic Drugs to Acidic Phospholipids Using Surface Plasmon Resonance and Incorporation of the Data into Mechanistic Tissue Composition Equations to Predict Steady-State Volume of Distribution

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