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5
PHARMACOKINETICS FOR
MEDICINAL CHEMISTS
LEONID (LEO)KIRKOVSKY AND ANUP ZUTSHI
5.1 INTRODUCTION
The purpose of this chapter is to give medicinal chemists a brief overview of the theory
of pharmacokinetics followed by some practical considerations that need to be taken
into account for planning PK studies and interpreting and troubleshooting PK data.
The primary focus of the chapter is using PK studies in discovery settings because this
stage of the drug invention and advancement is most relevant to medicinal chemists.
This chapter will not provide a comprehensive overview of PK theory and practices
but rather give junior medicinal chemists and other scientists with less experience
with PK a flavor of the challenges and considerations in using animal PK data.
5.1.1 History of Pharmacok inetics as Science
The term pharmacokinetics (from the Greek “pharmacon” meaning drug and
“kinetikos” meaning putting in motion) is a branch of pharmacology that involves
the rates of movement (disposition) of a drug (or any other substance) when
administered to a living organism. Specifically, pharmacokinetics is the study of the
rates of absorption, distribution, metabolism, and excretion of a drug (ADME) once
it is administered to a living organism.
Pharmacokinetics (PK) describes what the body does to the drug and is dependent
on the dose administered, site of administration, and physiological state of the
organism. A typical PK study involves administering a fixed amount of the drug
(the dose) to the subject (human or animal) and at various times postdose, samples of
ADMET for Medicinal Chemists: A Practical Guide, Edited by Katya Tsaioun and Steven A. Kates
Copyright 2011 John Wiley & Sons, Inc.
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an easily accessible tissue (usually blood/plasma) are drawn and collected for analysis
of the drug and its metabolite(s) concentrations. These concentration values are
plotted against the sampled times and the data mathematically analyzed to yield
parameters that are associated with the disposition of the drug.
Toxicokinetics (TK) is pharmacokinetics applied to high doses used in toxicity
testing of drugs. Sometimes such high doses result in a saturation of kinetic (mass
transfer) pathways, which can affect the PK profile.
Clinical pharmacokinetics is pharmacokinetics applied to clinical situations and
the therapeutic management of patients.
Population pharmacokinetics is the study of the sources and correlates variability
in drug concentrations among individual patients (inter- and intraindividual variability) such that, if necessary, dose adjustments can be made to offset the variability
and maximize therapeutic benefit.
The term pharmacokinetics was first coined by F.H. Dos t in 1953 and presented on
page 244 of his now famous treatise Der Blutspiegel (Blood Levels)—Kinetic der
Knozentrationsablaufe in der Kreislauffussigkeit [1]. The concepts of PK, however,
were known almost a 100 years prior to Dosts definition. Table 5.1 assimilates a
historical record of the discipline.
5.2 ADME
As described earlier, the acronym ADME is absorption, distribution, metabolism,
and excretion and is used to describe the various physiological processes in sequence
that the drug substance encounters from its initial input (dosing) to its final removal
from the body. The “E” in the acronym is excretion and not, as sometimes mistakenly
presented, elimination. In fact, metabolism and excretion together are elimination and
many texts may refer to the process as ADE whe re the “E” is elimination.
5.2.1 Absorption
Absorption is the process of movement of a drug from an extravascular site of
administration (such as the GI tract for PO, subcutaneous site [SC], intramuscular
[IM], rectal, inhalation [INH], etc.) into the systemic circulation (blood). Although,
there are great similarities between biomembranes in the GI tract and othe r tissues, the
absorption behavior of drugs from each of these sites can be very different.
5.2.1.1 Parenteral Routes of Administration (IM, SC) Absorption by the intramuscular route is very consistent and predictable and relatively fast. In cases where
drug cannot be administered by an IV route, however, a rapid delivery into the
systemic circulation is desired, IM is the preferred route.
In subcutaneous administration, the drug is injected into the tissue just under the
skin. Typically a larger volume of drug (10 mL/kg [3]) can be administered in the SC
space and sometimes if necessary, multiple SC injections can be made at different
sites in the body to increase availability. Typically, the absorption from the SC site is
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slow and usually similar to an orally administered dose. Drugs that are needed for
prolonged exposure in the body are preferably dosed via this route as are drugs that
have a nonaqueous (less polar) formulation.
5.2.1.2 Inhalation Route of Administration The inhalation route is employed for
local delivery of drugs to the lungs (bronchodilation, inflammation) or as a portal for
systemic delivery of the drug. Absorption from the lungs is very rapid and sometimes,
particularly for small molecular weight compounds (<1000 Da), almost as quick as an
IV dose. This is because the lungs are highly perfused, particularly in the alveolar
regions and drugs deposited in this region are rapidly absorbed.
5.2.1.3 Topical Route of Administration Drugs administered topically are usually meant for local application and therapy. Thus drugs for opthalmic, nasal, vaginal,
ear, and skin have a local effect and utility. The skin has been used to deliver drugs to
the systemic circulation (transdermal delivery). Although the transdermal route
TABLE 5.1 The Historical Milestones in Pharmacokinetics
Year Author Achievement
1847 Buchanan Showed that the anesthetic effect (depth of
narcosis) of ether was related to its brain
concentration, which in turn depended on
the arterial concentration and the strength
of the ether in the inhaled mixture
1847–1924 Sollman, Hanzlik,
Haggard, and others
Quantitative study of the disposition
kinetics of various chemicals in animals
1913 Michaelis and Menton Mathematical treatment of enzyme kinetics
1924 Widmark and Tandberg Defined one-compartment model
1924 Haggard Studied the disposition of diethyl ether
1931 Jolliffe Introduced the concept of clearance
1932 Hamilton Mean residence time
1934 Dominguez and Pomerone Volume of distribution
1937 Teorrell Multicompartmental PBPK model
1945 Oser Bioavailability
1948 Boxer Multiple dosing model
1953 Dost Introduced the term pharmacokinetics
1960 Perl Multiexponential curve fitting to PK data
1960 Garrett and Wiegand Use of an analog computer for curve fitting
and simulations
1961–1972 Wagner, Garrett, Levy,
Riegelman, Yaffe,
Nelson, Ritschel
The growth period of pharmacokinetics
when most of the terms and methods
were established and concepts defined
1965 Krueger-Thiemer Multiple dosing therapeutic model
1972 Levy and Gibaldi Defined clinical pharmacokinetics
1977 Sheiner Introduced population pharmacokinetics
Source: Adapted from Ref. 2.
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suffers from more variability in absorption than the other routes of administration,
many drug preparations have been developed for delivery through the skin. The
transdermal route is a noninvasive route and is suitable for patients that cannot
consume a drug through other routes. It also enjoys a higher compliance profile for
usage among patients.
5.2.1.4 Oral Route of Administration The oral route of drug delivery is the most
common, convenient, and widely used route of administration. Absorption from this
route varies with the region of the GI tract as the physicochemical nature of the GI tract
is very different in the stomach, duodenum, small intestine, and large intestine.
The pH, surface area, composition of the GI tract membr anes, presence and
absence of transporters, and presystemic P450s and other metabolizing enzymes,
presence and absence of bile, presence and absence of food, and a host of other factors
can influence the absorption of the drug.
Once absorbed, the drug is brought to the liver via the hepatic-portal vein and if the
drug is susceptible to first pass effects, the drug may be cleared before it reaches
the systemic circulation. All the mesenteric blood supply (from the entire GI tract
except for a small region close to the anal opening where the drug can directly access
the systemic circulation) collects into the hepatic-portal vein, thereby bringing the
absorbed drug in direct contact with the liver.
5.2.1.5 Enterohepatic Recycling Drugs and or their metabolites that pass into the
bile and are excreted into the intestine have the potential to be reabsorbed into the
systemic circulation. This transfer of drug from the body to the intestine and back into
the body is called enterohepatic recycling (EHR) [4].
Although all drugs that are excreted through the biliary pathway have the potential
to be recycled, the drug or its metabolite must possess certain physicochemical
characteristics for EHR to occur. Thus the drug or metabolite must be polar and have a
molecular weight greater than 350 Da. Many glucouronide metabolites (morphine,
naloxone, etc.) are excreted through the bile and into the intestine. The alkaline
environment of the intestine hydrolyzes the glucouronide and the released parent
molecule is reabsorbed into the systemic circulation.
5.2.2 Distribution
Distribution is the reversible transfer of drug molecules from one part of the body to
the other (Figur 5.1). The blood and to a smaller extent the lymph are the major tissues
responsible for distributing the drug molecules from one location of the body to
another.The ability of a drug molecule to distribute into tissues depends on the affinity
of the drug and its partitioning into the tissues, the strength of binding to the blood
components (RBCs, plasma proteins, platelets, etc.), and the physiological volume of
the tissue.
The PK parameter that characterizes the distribution of the drug is the volume
of distribution (V
d
). Although this parameter does not have any true physiological
relevance (the volume measure is not related to any body space), it does give a
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qualitative assessment of the extent of distribution (and the dilution of the dose).
Further details are provided in Section 5.4.1.3.
5.2.2.1 Plasma Protein Binding Since the blood is the major tissue that transports
drugs from one part of the body to the other, the components of blood can interact
with the drug. Plasma proteins comprise a significant fraction of plasma (8%) and
drugs usually bind to these proteins in a reversible manner (irreversible binding is
considered to lead to toxicity). This reversible binding of the drug to the proteins in
plasma is called the plasma protein binding (PPB).
It is acknowledged that drug bound to proteins is not available for interacting with
the target of action and is also not available for metabolism (clearance [CL]) and
excretion. However, PPB is an equilibrium and like any other equilibria, PPB obeys
the law of mass action. If the drug has an affinity for a target over the plasma protein,
the drug will partition into the target. Similarly, the drug may be readily cleared even if
the PPB is high (Figure 5.2).
Predicting PPB is difficult and hence trying to chemically modify a drug compound
to increase or decrease its PPB is a futile exercise. Instead, discovery programs should
focus on increasing the affinity of the drug to the target and reducing its CL liabilities
rather than trying to manipulate the PPB.
In discovery, the PPB is determined in all the preclinical species being investigated.
If the values for PPB are similar between the species, then correcting for free fraction
is not necessary as the inf ormation gained from using total or free concentrations on
the values of parameters is the same. If the values between the species are different,
then it is important to convert all concentrations and parameter estimates to the
corresponding free estimates for comparisons and decision making.
If it has been determined that the PPB varies in different species (rat, dog, monkey,
human, etc.), it appears prudent to measure the PPB in different strains of the same
species. If different strains of mice (CD-1, BALB/c, DBA, Swiss-Webster, etc.) or rats
(Sprague-Dawley,Wistar, Lewis, etc.) are being used for different studies on a project
and the PPB is different in these strains, then PPB should be determined in each strain
and the free concentrations or free parameter estimates should be used.
Figure 5.1 Schematic representation of the pharmacokinetic distribution of drugs (www.
stjude.org/SJFile/pharmaco_pharmacokinetics.pdf).
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Additionally, PPB may decrease with the increasing drug concentration in the
systemic circulation, particularly if the therapeutic levels of the drug approach the
concentrations of the primary binding components in the human plasma, albumin
(670 mM), or a 1-acid glycoprotein (16 mM) [5]. For the vast majority of drugs binding
to albumin, the therapeutic levels are significantly below the albumin concentrations
and consequently the PPB remains constant in each subject for a broad range of
administered doses . However, if the drug target protei n is present in the plasma along
with the plasma proteins, the saturation of some high-affinity but low-capacity
proteins may occur at therapeutic doses that subsequently can lead to a change in
the PK properties of the compounds at high and low doses. This has been reported for
the angiotensin-converting enzyme (ACE) inhibitors RU44403 [6] and ramipril [7]
and dipeptidyl peptidase 4 inhibitor BI-1356 [8]. Nonetheless, the clinical relevance
of the changes in PPB needs to be carefully evaluated [9]. Some additional discussion
of the PPB of drugs can be found in the following review articles [10–13].
In cases where data from a PK study is being compared with data from a
toxicology study, the concentration ranges may impact the PPB. It is recommended
to determine the PPB at various concentrations to help bridge the divide bet ween the
low concentr ations used in efficacy studies and the high concentrations used in
toxicology studies. If there is a PPB difference, the free concentrations should be
compared.
5.2.2.2 Red Blood Cell Partitioning Another major component of blood is the red
blood cell (RBC). Many drugs can partition or bind to the RBCs and similar to PPB are
considered unavailable to elicit a pharmacodynamic response or for clearance.
RBC distribution has been used as a carrier system for some anticancer drugs.
However, for most compounds the impact of RBC partitioning is small. It must be
determined for each species and if different, must be used to normalize concentration,
efficacy, and toxicology data.
D + P
DP
R
DR
+
DRUG-PROTEIN
INTERACTION
DRUG RECEPTOR
INTERACTION
ELIMINATING
ORGAN
Figure 5.2 Competing equilibria depicting the importance and relevance of PPB.
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In some instances, the extent of RBC partitioning of the drug is large and rate
limiting (hemoglobin modifiers such as the clofibric acids, etc.). This may result in
treating the RBCs as a separate kinetic compartment [14].
5.2.3 Metabolism
The irreversible conversion or biotransformation of the compound into a relatively
more polar entity (usually) is called metabolism. This biotransformation is affected by
a number of enzymes. The major family of enzymes that is involved in metabolism of
xenobiotics are called the cytochrome P450s. These enzymes are found in many
different organs but the major presence and source of these enzymes is the liver, the
largest metabolizing organ in the body. The kidneys and lungs are other organs that
express cytochrome P450s as well as other drug-metabolizing enzymes. Other
enzymes such as conjugating enzymes (glucouronidase, sulfatase) mono-oxygenating enzymes, such as FMOs, dehydrogenases, etc. can also contribute to the
biotransformation of drug substances.
These metabolic processes convert the drug into a more polar entity (in mos t cases)
and prepare it for being excreted and removed from the body.
5.2.4 Excretion
Ultimately the absorbed dose has to be excreted. A fraction of the dose administered
orally that never gets absorbed passes unchanged into the feces and is not the subject
of this sections discussion.
5.2.4.1 Renal Excretion The kidneys play a significant role in excreting drugs
into the urine. Most of this excretion occurs by a passive process through the
glomerulus (glomerular filtration [GF]). The proximal and distal tubules are lined
with various organic anion and cation transporters that excrete (tubular secretion
[TS]) or reabsorb (tubular reabsorption [TR]) drugs from the circulation and urine,
respectively (Figure 5.3), by an active energy driven process. These transporters are
saturable (leading to nonlinear PK) at high concentrations. For drugs that
may compete for the same transporters for excretion, the potential for drug–drug
interaction exists, when these drugs are administered concomitantly. Renal excretion
requires that the drug be water soluble and have a relatively polar structure.
Analyzing urine data (applies for biliary data also) from a PK data analysis is
slightly different than for plasma. First, the urine is considered to be collected in the
bladder from which there is no return of drug back into the circulation. Second, the
urine samples are collected over an interval, usually in 0–4 h intervals, and during
this time the plasma levels are constantly changing. This makes it difficult to assign
a specific plasma level to the excreted amount in the urine. Although the urine
collecting interval can be shortened (to less than 4-h duration), there is a risk of
incomplete bladder emptying which can result in errors in the estimation.
For a drug being cleared unchanged through the kidneys, the amount of drug
(concentration of the drug in the urine sample multiplied by the volume of the urine
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