Limited Distribution in the Body

This simple idea is based on the fact that drugs can distribute throughout the whole body whereas their targets are limited to some organs. As an example, the liver receives almost 100% of the amount of the drug absorbed after oral administration and about 50% after the drug has reached the general circulation. Thus, a significant amount of drug is lost as a fraction distributed in organs where it is useless at best and toxic at worst. Considering that most effects, either pharmacological or toxic, are concentration dependent, the first option is to restrict as much as possible the distribution of the drug to the nontargeted organs. This can be achieved by decreasing its VD to the lowest value compatible with activity. A limited lipophilicity may also fulfill this goal by decreasing transfer through membranes.

Another possibility is to design chemical structures ionized at physiological pH, i.e., poorly transferable by passive diffusion, but such compounds should retain good oral absorption. An elegant solution is obtained with zwitterionic molecules, which are mostly ionized at plasma pH yet well absorbed from the gut. This is possible when the isoelectric pH of the compound falls within the range of pH variations inside the gut (e.g., cetirizine).21'22

Another way to avoid an extensive distribution is to design agents that are bound to plasma proteins (mostly to HSA or to AGP) with an association constant high enough to retain a large amount of drug inside the compartment of distribution of the protein. This design creates the conditions for a restricted distribution (the drug is characterized by a low VD) avoiding an extensive and ubiquitous distribution of the drug in the body but delivering it only to sites of high affinity.

Such a design redirects the quantitative distribution to selective targets provided that they have a higher retention power for the drug. More precisely, the leading parameter is the binding capacity (Ca) of the protein:


n being the number of available binding sites per mole of protein.

The right solution is to design a compound whose plasma Ca is high enough to prevent the drug from an extensive distribution, but lower than the Ca of the targeted sites. Another example adds to this design the transfer of the plasma-binding carrier and its bound drug to the pathological sites. This is illustrated by the kinetics of many nonsteroidal antiinflammatory drugs (e.g., profens, mefenamic acid, and oxicams), all of which are acidic drugs ionized at plasma pH and extensively bound to HSA, their corresponding ranging between 0.1 and 0.4 Lkg_ 1. The early inflammation process induces a vasodilatation and an increase in the capillary permeability followed by a plasma transudation including HSA and its bound drug. As a result, the distribution of the drug is directed to its target by the pathological process. When inflammation stops, the impermeability of the capillaries is restored and no further drug is transferred to the previously inflamed tissue.

The best solution to limiting drug distribution in the body remains the discovery of very effective and selective agents. This allows the use of small doses, and limits their amounts in nontarget tissues. Unfortunately, agents with optimal in vitro behavior rarely have the kinetic characteristics necessary to become a drug. Favorable cases are those encountered when the pathological process induces specific enzymes not found in healthy tissues, e.g., the pathological increases in dihydrofolate reductases (DHFRs) and tyrosine kinases (TKs). DHFR inhibitors include trimethoprim (an antibacterial agent), chloroguanide (an antimalarial agent), and methotrexate (an antitumoral agent) while TK inhibitors include the antitumoral agents imatinib, erlotinib, and geftinib. Other specific inhibitors of cell enzymes are the statins and the coxibs.

Specific markers of pathological states, especially of cancers, are generally used as tests for the diagnosis of the disease and the prognosis of its evolution. As they are secreted by the tumor, they may be considered as drug targets. Antibodies are generated against these markers; in some cases they are effective by themselves, and in other cases active drugs are linked to them and thus targeted to the tumor.

A limited distribution may be obtained when the selected targets of a drug and its potential toxic sites are located in separated organs. This is a likely possibility when the target cells are more easily reached from the blood flow than the toxic sites. This is seen with the Hl-antihistamines whose therapeutic targets are always on the external sides of intravascular cells, on circulating eosinophils and neutrophils, or on the internal wall of veins and smaller vessels, or in perivascular tissues (connective tissue and basophils).23 Thus, the kinetics of cetirizine and that of its eutomer levocetirizine24 show that one can avoid most intracellular side effects of Hl-antihistamines, namely inside the heart, brain and liver, by limiting their distribution to their therapeutic target sites. The VD of cetirizine, for example, is 0.4 Lkg_ 1, i.e., less than the exchangeable water volume. In other words, the idea is to avoid organ toxicity by limiting the access of the drugs to these organs.25 Other examples include ^-antagonists (antihypertensive agents acting on vascular targets), inhibitors of angiotensin-converting enzyme, and angiotensin II receptor antagonists. In these cases, an intravascular distribution is enough to reach their targets, whereas their distribution to tissues serves no purpose.

To summarize, the kinetics of drugs can be improved by developing molecules whose affinity for and activity toward their targets are as high as possible, with a significant but smaller affinity for plasma proteins and the lowest possible tissue affinity. Stable and Predictable Elimination Processes

The effects of a drug are limited in time by the efficacy of physiological clearing functions, namely:

• metabolism when the metabolites are inactive;

• bile secretion of active compounds (parent drug and/or metabolites) when they are excreted fecally without enterohepatic cycling; and

• urinary excretion of active compounds (parent drug and active metabolites).

The liver, kidneys, and lungs (mainly for volatile agents) are the major organs of elimination whose overall clearing activities are expressed by clearance. The respective roles of these organs are investigated by means of two parameters: the first is the fraction of administered dose that they inactive or excrete; and the second is the rate of these processes. Such data are needed for rational prescription of drugs and should be carefully observed by those who prescribe.

For many drugs, target and clearing organs are different. With the exception of some drugs such as diuretics and urinary antibiotics, most are cleared by the liver and/or the kidneys where they have no role to play. The liver and kidneys fulfill their elimination function by very different mechanisms. Metabolic transformations are mainly hepatic and are carried out by enzymes whose activity varies among humans (interindividual variability) and as a function of time for the same individual (intraindividual variability). The fact that these enzymes act on chemically very diverse drugs explains the occurrence of drug interactions when two drugs compete for the same enzymes. Frequently, a competitive interaction ensues where the metabolism of one is decreased by the other (potentiation). On the other hand, enzymatic induction or inhibition may also occur following administration of some drugs or intake of some foods (e.g., grapefruit). All these potential causes of variation explain why the duration of action of drugs when controlled by hepatic enzymes may differ among patients. Such a route of elimination thus brings a certain degree of uncertainty in the duration of action.

When a drug is excreted mainly unchanged in urine, the margin of uncertainty is lessened if renal functions are normal and the pH of urine is controlled. The most likely explanation of the differences between hepatic degradation and kidney excretion is linked to identical renal functions among individuals (creatinine clearance is a stable parameter, 120mLmin_ 1), whereas the activities of normal hepatic enzymes differ to a large extent. This observation remains true when renal functions are impaired. If the pathological process is stable with a decreased but stable creatinine clearance, it is possible to adjust drug dosage knowing the relationship between the clearance of the drug and creatinine clearance. This relationship is determined by specific pharmacokinetic studies including normal volunteers and patients with various degrees of renal insufficiency. This is done for instance for digoxin and aminoside antibiotics.

When a choice is possible, physicians are thus likely to prefer a drug excreted mainly unchanged in urine. To avoid hepatic metabolism as much as possible, one needs a low lipophilicity and sterically protected target groups in the molecule, inasmuch as these features are compatible with activity. This objective is valid for all drug classes for which no benefit can be expected from hepatic extraction. This is the case for drugs acting in peripheral organs, for example anti-inflammatory drugs, most antibiotics, antihypertensive agents, and Hl-antihistamines. However, it appears that this proposal cannot be applied to drugs acting in the CNS, which must be able to cross the blood-brain barrier and require a sufficient lipophilicity also synonymous with liver uptake (e.g., psychotropic drugs). Linear Pharmacokinetic Parameters

The main interest of pharmacokinetic parameters (CL, VD, t1/2, tmax) is that they are constants applicable to all doses. This argument, however, is restricted to drugs whose kinetics is linear. With nonlinear pharmacokinetics, the corresponding parameters vary according to dose. Nonlinearity may be the consequence of two main processes, namely, plasma binding or liver transformation. When the overall plasma concentrations of a drug increase beyond the upper limit of protein binding capacity, the excess of drug cannot be bound. Being free and completely distributed (saturation of the restricted distribution process), it induces an increase offu which leads to a modification of pharmacokinetic parameters: VD increases (see eqn [34]) and VD,u decreases (see eqn [35]). Moreover, CLR increases and when CLint is low, CLh increases (see eqn [26]) but CLHu is not affected. Another cause is a quickly saturated reaction of transformation, which leads to a decrease of CLH because CLH u decreases,fu being constant (see eqn [26]) and either results in accumulation or is replaced by an untoward transformation, for instance, into a toxic reactive metabolite (e.g., acetaminophen).

Nonlinear pharmacokinetics is a handicap for drug prescription. Schematically, infra- and suprasaturating doses exhibit different pharmacokinetic parameters due to different kinetics at enzymes or transporters. Changing doses from infra to supra will induce an increased effect, the intensity of which may be higher than expected.

In summary, the therapeutic use of drugs exhibiting nonlinear pharmacokinetics is not easy but cannot be rejected a priori. Indeed, the threshold concentration beyond which nonlinear processes begin varies among individuals according to their plasma binding capacity and liver enzymatic activities. A simple solution is to use only low, infrasaturating doses, a drug with linear kinetics remaining the best option when a choice exists. One Oral Dose Once a Day

The oral route is obviously the best route of administration especially when chronic treatment is needed. The rule 'one tablet once a day' is very well known, but it requires some specifications. Thus, absorption has to be almost complete, unmodified by food intake, stable according to time, and produce an effect of constant intensity for 24 h meaning that t1/2 should be adequate, close to 24 h. Specific formulations may fulfill this objective.

A pharmacokinetic solution to prolonging effects is to design a drug with a restricted distribution that is bound to HSA, and whose release from this protein is delayed. This is achieved with a low dissociation rate of the drug-protein complex, as successfully shown by some sulfonamides, which are active for 2 weeks after a single administration.

5.02.7 Which Pharmacokinetics for Populations at Risk?

Populations at risk involve apparently healthy people as well as those with health problems. The latter group includes the extremes of age, namely embryos, fetuses, newborns, children, and elderly persons. The second group includes patients presenting with either a disease that affects drug elimination or rapidly evolving multipathological processes. It is not possible here to propose specific pharmacokinetic profiles according to the encountered risk, but guidelines can be given to obtain the best benefit/risk ratio, as exemplified below.

During pregnancy, the amount of drug transferred through the placenta to the fetus is limited to the free drug plasma concentration of the mother. The rate of transfer follows Fick's law (eqn [1]). In this specific case, S is the placenta surface available for drug transfer, d is the thickness of this surface, and DC represents the gradient of plasma free drug concentrations between the mother and the fetus. During pregnancy, S increases and d decreases, and both modifications favor the transfer of drugs to the fetus. The consequence is that more drug is transferred to the fetus at the end of the pregnancy with a maximum at the time of delivery, S being then maximal and d minimal. From a pharmacological point of view, where extensive drug diffusion to the fetus needs to be avoided, one can reduce its transfer by decreasing the maternal-fetal gradient. This can be achieved by oral administration in small repeated doses distributed over the course of a day. In some specific and rare circumstances, the intravenous route may be used to reach a high gradient, i.e., when the drug must be administered to the fetus via the mother. But in most cases transfer of drug to the fetus is not wanted and can be limited by binding to maternal plasmatic proteins (restricted distribution). Use of such binding can also limit drug transfer to breast milk after delivery. Moreover, as the newborn will not have a functional blood-brain barrier (BBB) until 3 weeks after birth, a strong binding to plasma proteins can be useful to limit CNS distribution when not required therapeutically.

At birth, renal excretion and liver metabolism are not immediately functional but they improve progressively. Unfortunately, many drugs are not adapted to this age group, and clearly the physicians must favor drugs known to be quickly eliminated in adults. Special efforts to design adapted drugs should be encouraged.26

In the elderly, several physiological alterations can be observed.27 The adipose mass is increased even in lean people and liquid volumes are decreased. As a result, hydrophilic drugs will reach higher plasma concentrations and doses must be decreased accordingly. In contrast, lipophilic drugs are stored for longer periods inducing a longer duration of effects in the elderly as compared to adults, also increasing the risk of drug interactions. Moreover, the liver mass is reduced in elderly people and the number of functional hepatocytes is decreased accordingly; hence, metabolic processes are usually slower and hepatic clearance decreased especially when cytochrome P450 dependent since these enzymes are very sensitive to decreased protein synthesis. Conjugation reactions that occur in the cytosol appear to be less modified. This is why, for instance, hydroxylated benzodiazepines are preferred for elderly patients over those that are oxidized in vivo. More generally, drugs having a short t1/2 are preferable.

Elderly people frequently develop a chronic renal insufficiency (decreased renal clearance), a situation which must be taken into account when setting the doses of drugs excreted renally.

Hepatocellular insufficiency28 and chronic renal disease29 are the two main pathological states that induce a significant alteration of the kinetics of drugs (mainly decreased total plasma clearance). The knowledge of PK parameters in healthy subjects, and more precisely the respective roles of liver and kidneys in overall elimination processes, allows it to be anticipated whether drug elimination will be normal or decreased in a given pathological state. Thus, it is usual to prefer extensively metabolized drugs in cases of renal insufficiency and urine-excreted, unmetabolized drugs in those of hepatic diseases. This procedure is now questioned, as it appears that it is easier to adjust the dosage of a drug excreted in urine during renal insufficiency than to use a drug inactivated by liver enzymes. The best example of this is shown by digoxin and its alternative digitoxin. Digoxin is excreted mainly in urine without transformation (85%) and secondarily as hepatic metabolites (15%). Digitoxin is excreted mainly as inactive metabolites (85%) and partly in urine as the parent drug (15%). However, their t1/2 are 1.6 + 0.5 and 6.7+ 1.7 days for digoxin and digitoxin, respectively. Both have a low therapeutic index (2 or so) and a dose-dependent toxicity. Digoxin is selected despite renal insufficiency, as the risk of accumulation is lower with this drug than with digitoxin. Here again, renal excretion appears to be more easily controlled than liver metabolism.

It is not possible to define drug kinetics for emergency situations as the encountered pathological states differ vastly and evolve quickly. The selection of the intravenous route bypasses the absorption phase, which is a pharmacological lag phase. Emergency wards tend to use drugs whose effects are immediate and brief. These drugs are mainly hydrophilic, a requisite to intravenous injections, and are excreted by the kidneys.

5.02.8 Conclusion

Besides efficacy and safety, there is now a growing interest in other qualities expected from a new drug. Regularity of effects and facility of use are important factors that improve the quality of life. Adequate pharmacokinetic parameters help to achieve this. Considering the relevance of current pharmacokinetic tools, it is obvious that methodological progress is needed in the screening and evaluation of new chemical entities. One advance is a more precise evaluation of drug distribution in and between organs; VD affords an idea of drug concentrations in blood and organs, but it cannot establish in which of them the drug is predominantly located. Improvements will probably be afforded by new techniques such as imaging, which allows the respective locations of drugs and their specific targets to be observed using labeled markers and positron emission tomography (PET) scans. The location of a drug inside cells should also be studied, and the following need to be considered: binding to nuclei, which are the starting point of many pharmacological effects; binding to the endoplasmic reticulum as a regulator of Ca2 + homeostasis; and binding to mitochondria as the main source of energy transmission (ATP). Subcellular pharmacokinetics should also be developed.

A more ambitious yet realistic research trend involves avoiding the phase of vascular transfer by going directly to the site of action. One solution may be the direct application of drugs inside the targeted organs, permitting the use of high doses and limiting blood transfer and nonspecific distribution. Such projects need new technologies such as nanoparticles and probably new modes of administration adapted to each patient. These are some of the challenges for the near future.


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Jean-Paul Tillement is MD, PharmD MSc, Professor of Pharmacology. From 1985 to 2003 he held the position of Full Professor of Fundamental and Clinical Pharmacology and Head of Department at the Faculty of Medicine Paris-XII. His responsibilities during this time included teaching and research at the Faculty, as well as activities in clinical pharmacology as part of drug treatments of patients at the University Hospital as a qualified biologist Head of the Hospital Department of Pharmacology. He held various national appointments as an expert at the French Ministry of Health (still ongoing) and public research structures (INSERM, INRA), and at the French Ministry of Justice (still ongoing). Prof Tillement was also involved as an expert in the COST project, Brussels, Belgium (Criteria for the choice and definition of healthy volunteers and or patients for phase I and II studies in drug development, 1995). He has organized international scientific meetings especially on drug-protein interactions, his first recognized field of expertise, which he has in parallel broadened to include the pharmacological preservation of mitochondrial functions. He is past-president of the Société Francaise de Pharmacologie Clinique et Thérapeutique; past member of the jury of Prix Galien (1988-2005); current member of 10 medical and scientific societies; of the board of 9 international journals; current referee of 7 international journals; full member of the French National Academy of Pharmacy and corresponding member of the French National Academy of Medicine; Adjunct Professor at the Georgetown University Medical Center (Washington DC, USA) since 2002. He serves as a consultant in pharmacology to pharmaceutical companies. He has published more than 560 scientific works (December 2005) consisting in Research & Educational papers, Reviews and Books, Communications and Posters, and conducted 35 thesis.

Dominique Tremblay, PhD (Pharmacy), has obtained certificates in General and Human Biochemistry, and in Statistics Applied to Medical Biology, Clinical Pharmacology and Pharmacokinetics. From 1991 to 1998, he held the position of director of Preclinical Development at Hoescht-Marion-Roussel in Romainville (France). In this position he was in charge of the departments of Toxicology, Pharmacokinetics (preclinical and clinical), Quality, Pharmaceutics, Quality Assurance and Scientific Coordination and Documentation. He actively participated in the development and introduction of various drugs (antibiotics, hormones and antihormones, nonsteroidal antiinflammatory drugs, and cardiovascular drugs) into the international market. After he left Hoescht-Marion-Roussel, he became an expert in Pharmacokinetics, Toxicokinetics and Toxicology at the French medical agency (Agence Française de Sécurité Sanitaire des Produits de Santé, AFSSaPS). At present, he is a member of the Marketing Committee Authorization and chairman of the Preclinical Working Party at the AFSSaPS, and a member of the Safety Working Party at the European Agency for the Evaluation of Medicinal Products (EMEA). He gives lectures at the University of Paris on toxicokinetics and pharmacokinetics. He participates as a tutor in the Pharmacokinetic Workshop under the guidance of Professors Malcolm Rowland and Thomas Tozer. Dominique Tremblay's interests are in experimental and applied pharmacokinetics. He has published about 50 scientific publications, abstracts and posters in this area. His main field of interest is how pharmacokinetics and toxicokinetics can be best used to predict and/or understand the effects of drugs on both man and animal in terms of efficacy and safety.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 5) 0-08-044518-7; pp. 11-30

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