AbstractThe process of drug movement after absorption into various body compartments like the interstitial space and the intracellular space is called drug distribution. Distribution is an important process which results in exposure of the target organ to the drug. The initial phase is highly influenced by the amount of blood flow to various organs and is responsible for the acute onset action of the drugs. The second phase is a slower phase where the drug equilibrates with the muscle, skin, and fat. The second phase can be responsible for the termination of action for some of the drugs. The cardiac output, local regional blood flow, alterations in capillary permeability, plasma protein binding, the local pH, and affinity to tissue proteins are some of the factors that influence drug distribution. Increase in plasma protein binding results in lower volume of distribution, longer duration of action, and slower onset of action. Plasma protein binding is responsible for displacement reactions and drug interactions. Excessive tissue protein binding can result in organ toxicities. To some extent, distribution can be quantified by the apparent volume of distribution. The volume of distribution helps us determine the loading dose of drugs which are required in emergency settings. Show
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Rights and permissionsCopyright information© 2019 Springer Nature Singapore Pte Ltd. About this chapterCite this chapterPaul, A. (2019). Drug Distribution. In: Raj, G., Raveendran, R. (eds) Introduction to Basics of Pharmacology and Toxicology. Springer, Singapore. https://doi.org/10.1007/978-981-32-9779-1_6 Download citation
Pharmacokinetics (PK) is the study of how a drug moves throughout the body and provides important information on the systemic exposure to the drug over time. Conversely, pharmacodynamics (PD) describes what a drug does to the body, meaning, the pharmacologic response that occurs when a drug has reached the site of action. In order to collect relevant PK and PD data for a drug, clinical studies must be conducted which help determine the onset, magnitude, and duration of a drug’s effect. Together, PK and PD data can be used to describe the safety and efficacy of a drug by establishing dose-exposure-response relationships. Any given drug may behave differently in different patients due to biological variability. Patient-specific factors that influence the way drugs are processed include intrinsic factors such as age, weight, sex, and genetics. There is also typically variability between patients in both the minimum plasma concentration of drug needed to produce a desired pharmacological response and the maximum plasma concentration of drug that can be tolerated without unacceptable toxicity. Therefore, designing an optimal dosing regimen based on PK and PD data is important to ensure that the majority of patients will attain the proper therapeutic exposure range that does not cause intolerable side effects. This can be accomplished by examining a drug’s PK through the processes of absorption, distribution, metabolism, and excretion. The Pharmacokinetics Process: ADMEAbsorption, distribution, metabolism, and excretion, also known as “ADME,” are the internal processes that describe how a drug moves throughout and is processed by the body. ADME is assessed through the collection of data in clinical pharmacology studies and helps explain the PK processes at play for any given drug. Understanding the ADME properties of a drug is essential to the development of a safe and effective pharmacotherapy. AbsorptionAbsorption happens when a drug travels from the site of administration to the systemic circulation system – which provides functional blood supply to all body tissues. The extent of absorption into the bloodstream can be described by bioavailability, which is defined as the fraction of drug that reaches the site of action. For example, drugs that are taken through an oral route of administration often pass through the small intestine and liver, where some amount of the drug is eliminated prior to reaching the bloodstream. This results in a reduction of the amount of drug delivered to the site of action and therefore decreased bioavailability. Drugs that are administered intravenously are delivered directly to the bloodstream and have a bioavailability of 100%. As a result, absorption is not measured for intravenously administered drugs. Food effect PK studies are often conducted for orally administered drugs and may provide information on a drug’s absorption based on the impact of high fat meals, low fat meals, and fasted states. When necessary, studies with gastric acid-reducing agents may also be conducted to determine if a clinically significant drug-drug interaction (DDI) should be anticipated as a result of concomitantly administered drugs that elevate gastric pH. Some factors that can affect the rate and extent of drug absorption include:
DistributionAfter a drug is absorbed, it is then distributed throughout the body. Distribution describes the process of a drug traveling into different organs and tissues and depends on a multitude of factors including fluid status, blood flow, and chemical characteristics of the drug. Distribution is measured by a fundamental PK parameter known as the volume of distribution. Volume of distribution describes the amount of drug present in the tissues versus in the blood and is important in determining half-life and dosing regimen. Another important consideration to the distribution process is protein binding. When a drug enters the circulatory system, it may become bound to plasma proteins such as albumin, the most abundant plasma protein. Protein binding acts as a “holding station,” rendering the drug pharmacologically inactive while bound. For a drug to achieve its expected pharmacological response, it must be free (unbound to a plasma protein) and reach the site of action at a designated receptor site. Drugs must also be unbound in order to be metabolized. MetabolismOnce a drug has been absorbed and is distributed throughout the body, metabolism occurs. Drug metabolism is the process of chemically altering the molecules of a drug, which creates new compounds. The compounds created from this process are known as metabolites. Metabolism may occur in many areas of the body including the gastrointestinal tract, kidneys, and plasma, but the majority of metabolism occurs in the body’s largest internal organ, the liver. In the liver, there are many enzymes that can process drugs via Phase 1 and Phase 2 metabolic pathways. Metabolites formed from Phase 1 reactions are more likely to be pharmacologically active. In contrast, Phase 2 reactions generally render a compound more water soluble and pharmacologically inactive. Although the metabolism of drugs generally decreases their pharmacologic activity, there are some drugs, known as prodrugs, that must undergo metabolism to become active. Prodrugs are often designed to improve certain ADME characteristics of a specific parent drug in order to increase the benefit of the drug for the patient. Cytochrome P450 (CYP) enzymes are responsible for a large percentage of the metabolism of commonly used drugs. CYP-mediated drug metabolism facilitates the elimination of drugs from the body and plays an important role in drug safety and activity. CYPs contribute to variability in drug response and can be impacted by concomitant medications, which can lead to DDIs. Some factors that can affect drug metabolism include:
ExcretionAny drug that is not eliminated from the body via metabolism is eliminated via excretion. Although drugs can be excreted by a variety of different routes including the liver, lungs, gastrointestinal tract, and skin, the most common pathway of excretion is through the kidneys. When a drug is primarily excreted via the kidneys, impaired kidney (renal) function can significantly affect a drug’s PK. One type of change in the PK of a drug that can occur as a result of impaired renal function is a decrease in the excretion of the drug or a decrease in the excretion of metabolites of the drug. If a drug is not being excreted properly due to renal dysfunction, drug accumulation in the body and potential toxicity can occur. Therefore, in many programs, it is important to characterize PK in renally impaired subjects in order to provide proper dosing recommendations specific to that patient population. Adjusting dosing regimens in patients with renal impairment can help prevent accumulation at steady-state, especially for drugs with a narrow therapeutic index, thus limiting adverse effects in this vulnerable population. Some other factors that can affect drug excretion include:
Why Pharmacokinetic Studies Are ImportantPK studies allow the characterization of ADME properties of a drug early in development. They also provide critical information including the impact of food interactions (in orally administered drugs), drug-drug interactions, and organ impairment on the disposition of a drug. The foundational information gained from PK studies help guide what additional studies are needed, as certain types of clinical studies may not be helpful or relevant for all drugs. PK studies also help identify proper dosing for future studies and real-world use. PK data should be collected both early and later in development to further elucidate the ADME properties of a drug in larger study populations. Collection of PK data provides an opportunity to assess important information on factors that could cause variability in drug exposures that may lead to compromised safety or efficacy. Factors that can cause inter-individual variability (variability observed between individuals) or intra-individual variability (variability observed within the same individual) must be identified in order to design the optimal dosing regimen. Researching the PK properties of a drug early-on (and throughout) development ultimately allows for a higher likelihood of downstream success both in clinical studies and in real-world patients. ConclusionsSmarter drug development starts with designing your program around a solid understanding of pharmacokinetics. A clear picture of the PK and ADME properties of a drug is essential for the FDA and other regulatory bodies to understand a drug’s safety, efficacy, and other factors related to patient use. Nuventra is a leading PK science consulting group in the industry. Our specialized focus in PK, PD, and clinical pharmacology helps our clients avoid costly missteps in drug development. Contact us today to learn more about how our variety of PK analyses services can benefit your program. Contact Us AcknowledgementsAlex Jones, PharmD candidate, served as a coauthor for this blog under the guidance of Rachel Tyson, Pharm.D., Clinical Pharmacologist II What is the movement of drugs through the body called?Pharmacokinetics, sometimes described as what the body does to a drug, refers to the movement of drug into, through, and out of the body—the time course of its absorption.
Is the process of drug movement to achieve drug action?Pharmacokinetics is the process of drug movement to achieve drug action. The four processes are absorption, distribution, metabolism (or biotransformation), and excretion (or elimination). The nurse applies knowledge of pharmacokinetics when assessing the patient for possible adverse drug effects.
What is the process of drug distribution?Drug distribution is the disbursement of an unmetabolized drug as it moves through the body's blood and tissues. The efficacy or toxicity of a drug depends on the distribution in specific tissues and in part explains the lack of correlation between plasma levels and the effects that are seen.
What is the process of drug absorption?Absorption is the process of delivering a drug into the blood stream. Absorption can be accomplished by administering the drug in a variety of different ways (e.g. orally, rectally, intra-muscularly, subcutaneously, inhalation, topically, etc.).
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What is the process of drug movement throughout the body that is necessary to achieve drug action?
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