Pharmacokinetics and Metabolism in Drug Design

Dennis A. Smith, Charlotte Allerton, Amit S. Kalgutkar, Han van de Waterbeemd, Don K. Walker, Dennis A. Smith, Charlotte Allerton, Amit S. Kalgutkar, Han van de Waterbeemd, Don K. Walker, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

• Publisher: Wiley-VCH
• Year: 2012
• Print ISBN: 9783527329540
• eBook ISBN: 9783527645299
• Edition: 3
• Topic: Medicine
• Subtopic: Pharmacology

In this new edition of a bestseller, all the contents have been brought upto-date by addressing current standards and best practices in the assessment and prediction of ADMET properties. Although the previous chapter layout has been retained, substantial revisions have been made, with new topics such as pro-drugs, active metabolites and transporters covered in detail in a manner useful to the Drug Discovery scientist. The authors discuss the parameters and processes important for the absorption, distribution and retention of drug compounds in the body, plus the potential problems created by their transformation into toxic byproducts.

While aimed at all those dealing professionally with the development and application of pharmaceutical substances, the readily comprehensible style makes this book equally suitable for students of pharmacy and related subjects. Uniquely comprehensive, the book relates physicochemistry and chemical structure to pharmacokinetic properties and ultimately drug efficacy and safety.

Chapter 1

Physicochemistry

Abbreviations

CPC	Centrifugal partition chromatography
CoMFA	Comparative field analysis
CsA	Cyclosporine A
3D-QSAR	Three-dimensional quantitative structure–activity relationships
HDM	Hexadecane membrane
IUPAC	International Union of Pure and Applied Chemistry
MLP	Molecular lipophilicity potential
PAMPA	Parallel artificial membrane permeability assay
PGDP	Propylene glycol dipelargonate
PSA	Polar surface area
RP-HPLC	Reversed-phase high-performance liquid chromatography
SF	Shake flask, referring to traditional method of measuring log P or log D
TPSA	Topological polar surface are

Symbols

APSUV	Absorption potential measured in small unilamellar vesicles (SUV)
Δlog D	Difference between log D in octanol/water and log D in alkane/water
Δlog P	Difference between log P in octanol/water and log P in alkane/water
f	Rekker or Leo/Hansch fragmental constant for log P contribution
Ka	Ionization constant
Λ	Polarity term, mainly related to hydrogen bonding capability of a solute
log P	Logarithm of the partition coefficient (P) of neutral species
log D	Logarithm of the distribution coefficient (D) at a selected pH, usually assumed to be measured in octanol/water
log Doct	Logarithm of the distribution coefficient (D) at a selected pH, measured in octanol/water
log Dchex	Logarithm of the distribution coefficient (D) at a selected pH, measured in cyclohexane/water
log D7.4	Logarithm of the distribution coefficient (D) at pH 7.4
MW	Molecular weight
π	Hansch constant; contribution of a substituent to log P
pKa	Negative logarithm of the ionization constant Ka

1.1 Physicochemistry and Pharmacokinetics

The body can be viewed as primarily composed of a series of membrane barriers dividing aqueous filled compartments. These membrane barriers are principally comprised of the phospholipid bilayers that surround cells and form intracellular barriers around the organelles present in cells (mitochondria, nucleus, etc.). These are formed with the polar ionized head groups of the phospholipid facing toward the aqueous phases and the lipid chains providing a highly hydrophobic inner core. To cross the hydrophobic inner core, a molecule must also be hydrophobic and able to shed its hydration sphere. Many of the processes of drug disposition depend on the ability or inability to cross membranes and hence there is a high correlation with measures of lipophilicity. Moreover, many of the proteins involved in drug disposition have hydrophobic binding sites further adding to the importance of the measures of lipophilicity [1].

At this point, it is appropriate to define the terms hydrophobicity and lipophilicity. According to published IUPAC recommendations, both terms are best described as follows [2]:

Hydrophobicity is the association of nonpolar groups or molecules in an aqueous environment that arises from the tendency of water to exclude nonpolar molecules.

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic environment. It is commonly measured by its distribution behavior in a biphasic system, either liquid–liquid (e.g., partition coefficient in 1-octanol/water) or solid–liquid (retention on reversed-phase high-performance liquid chromatography or thin-layer chromatography (TLC) system).

Key physicochemical properties that are associated with hydrophobicity and lipophilicity include solubility, hydrogen bonding capacity, and the ionization state [3]. All these properties have a strong influence on membrane permeability that affects absorption [4], distribution, and balance of elimination by transporter-mediated processes and metabolism [5].

1.2 Partition and Distribution Coefficients as Measures of Lipophilicity

The inner hydrophobic core of a membrane can be modeled by using an organic solvent. Similarly, a water or aqueous buffer mimics the aqueous media surrounding cells or present within cells. If the organic solvent is not miscible with water, then a two-phase system can be used to study the relative preference of a compound for the aqueous (hydrophilic) or organic (hydrophobic and lipophilic) phase.

For an organic compound, lipophilicity can be described in terms of its partition coefficient P (or log P as it is generally expressed). This is defined as the ratio of concentrations of the compound at equilibrium between the organic and the aqueous phases:

(1.1)

The partition coefficient (log P) describes the intrinsic lipophilicity of the collection of functional groups and carbon skeleton, which combine, to make up the structure of the compound, in the absence of dissociation or ionization. Methods to measure partition and distribution coefficients have been described [6, 7].

Every component of an organic compound has a defined lipophilicity, and calculation of partition coefficient can be performed from a designated structure. Likewise, the effect on log P of the introduction of a substituent group into a compound can be predicted by a number of methods as pioneered by Hansch [8–11] (π-values), Rekker [12, 13] (f-values), and Leo and Hansch [8–10, 14, 15] (f ′-values). These values break molecules down into fragments allowing the total lipophilicity to be calculated.

Partitioning of a compound between aqueous and lipid (organic) phases is an equilibrium process. When in addition the compound is partly ionized in the aqueous phase, a further (ionization) equilibrium is set up since it is assumed that under normal conditions only the unionized form of the drug penetrates the organic phase [16]. This traditional view is shown schematically in Figure 1.1.

Figure 1.1 Schematic depicting the relationship between log P and log D and pK_a.

This model is consistent with many observations, but partitioning of some compounds into octanol has been shown to occur as an ion pair [17]. Such ion pairs include chloride with basic compounds and sodium with acidic compounds. Whether such behavior can occur with a biological membrane is still not clear, some evidence exists for this with the strongly acidic drug proxicromil. The lipophilicity of the drug above pH 6 in octanol–buffer partition experiments depends on ion p...

Table of contents

• Cover
• Methods and Principles in Medicinal Chemistry
• Title Page
• Copyright
• A Personal Foreword
• Chapter 1: Physicochemistry
• Chapter 2: Pharmacokinetics
• Chapter 3: Absorption
• Chapter 4: Distribution
• Chapter 5: Clearance
• Chapter 6: Renal Clearance
• Chapter 7: Metabolic (Hepatic) Clearance
• Chapter 8: Toxicity
• Chapter 9: Predicting Human Pharmacokinetics
• Chapter 10: ADME Screening
• Index