Absorption, distribution, metabolism, and excretion are processes that together describe a drug’s overall disposition via pharmacokinetics, or what the body does to a drug. ADME data can be collected at many stages in a drug’s development pipeline. In discovery and lead optimization, drug developers may make chemical modifications to drug candidates to optimize ADME properties1. As a drug moves forward through preclinical development and clinical phases, in vitro and in vivo studies provide critical information needed to meet regulatory expectations and equip drug developers to make informed decisions. Show AbsorptionAbsorption is the process by which a drug enters the bloodstream. There are many possible routes of administration, but the two most common are intravenous and oral. If a drug is administered intravenously, the absorption phase is skipped as the drug immediately enters circulation. However, many drugs are dosed orally because it makes it possible for patients to self-administer. When a xenobiotic is ingested, it travels first through the gastrointestinal tract, then to the liver via the portal circulation, and from there enters systemic circulation during which it can be distributed to the site of action. Small molecules typically traverse membranes throughout this process, sometimes via passive transport, but often by way of proteins known as drug transporters. Drug transport can be a critical component of a drug’s disposition in many steps of the pharmacokinetic journey, and preclinical studies should be conducted to provide information on how a drug interacts with various transporters – as either substrates or inhibitors. A drug’s absorption may be impacted by many factors, including molecular weight, topological polar surface area (TPSA), solubility, ionization, and other physicochemical properties. Importantly, absorption data can be helpful in determining the potential for how much of the drug reaches the bloodstream after oral administration. The first-pass effect (among other factors) after oral absorption will ultimately determine bioavailability. DistributionDistribution describes the reversible transfer of a drug from one location in the body to another. Drug developers can get a big-picture view of drug concentration in various tissues and organs over time from radiolabeled in vivo ADME studies, including quantitative whole body autoradiography (QWBA), microautoradiography (mARG), and tissue dissection. Other in vitro studies can help piece together the more minute details of a compound’s distribution. For example, permeability assays can characterize the potential of a compound to enter cells, drug transporter studies help to identify proteins responsible for moving a drug into (uptake) and out of (efflux) cells, and plasma protein binding (PPB) studies quantify the extent of binding to plasma proteins, which could limit the amount of free drug available for therapeutic action or interaction with transporters or enzymes.  MetabolismMetabolism is the conversion of generally more lipophilic xenobiotic compounds to hydrophilic metabolites that can be eliminated from the body via excretion2. Metabolism of a drug involves enzymes and several investigative studies may be needed to identify major metabolites and relevant metabolic pathways. There are a few primary drug metabolism studies performed in vitro to validate major players in a drug’s metabolism and meet regulatory submission expectations. These studies include metabolic stability to predict a drug’s in vivo half-life, metabolite characterization and identification across species to elucidate metabolites formed and determine if any are unique to humans or disproportionately higher in human than preclinical species, and reaction phenotyping studies to provide insight to which enzymes are responsible for metabolism. By the time a sponsor is conducting animal studies, they often have already identified metabolic pathways, enzymes, and metabolites from earlier in vitro data and can use animal ADME studies to corroborate choices and strengthen correlation between in vitro predictive data and in vivo/clinical results. Metabolite identification studies are a typical component of an in vivo ADME package, using LC-MS or radiolabeled compound to identify and possibly quantify metabolites in plasma and excreta from treated animals at successive time points. Metabolite identification can be done then again during clinical trials— plasma, urine, etc. from treated humans can be analyzed using the same methods provide supportive data on which human metabolites are found clinically. ExcretionExcretion is the irreversible loss of a substance from the system. In most cases, all drug-related material, including parent drug and metabolites are eventually cleared from the body. It is important to characterize which routes of excretion are most important. Excretion commonly occurs by function of the kidney (urine) or liver (bile/feces), but the drug can also be excreted through sweat, tears, or breath. In vivo excretion studies can help to both identify route(s) of excretion of a compound and characterize drug-related material clearance while monitoring the exposure of drug and metabolites in plasma and other compartments. Animal mass balance studies use radiolabeled compound to characterize a drug’s excretion path and rate. From this study, quantitative analysis of urine, feces, (in some cases) expired air, and carcass provide a complete picture of how a compound is eliminated from the body and at what rate. Other supportive studies can provide data to further explore biliary excretion (bile duct cannulation method), lymphatic partitioning rate, excretion via milk, and more. Big Picture: ADME helps drug developers to distinguish ‘good’ drug candidatesPotential drugs need appropriate pharmacokinetic properties to become safe, useable, effective therapeutics. In order to have a ‘good’ pharmacokinetic profile, a drug must:
We offer test systems and contract services to clients who need high-quality, dependable in vitro and in vivo ADME data. In addition to utility in understanding pharmacokinetics of your drug and meeting regulatory requirements for IND submission, ADME data can be used to support or precede studies investigating drug-drug interaction (DDI) potential of a compound. By ensuring your drug is supported by well-designed, carefully executed preclinical studies, you can maximize your drug’s chance of success in the clinic. Our team has been building experience for 25 years; our experts have just about seen it all. When it comes to your compound’s in vitro and in vivo ADME data, we can offer you quality, reliability, and a consultative approach. References
Next Up: Concepts Related to a Compound’s ADME
In vitro preclinical testing methods to predict your drug’s risk of causing a metabolism- or transporter-mediated drug interaction in clinical phases.
Biotransformation pathways and metabolite formation provide critical information to the safety profile of an investigational new compound. DMPK is a discipline in which sponsors can understand how a drug’s metabolism and pharmacokinetics impact safety considerations and overall disposition.
Drugs must get to their site of action to be useful, and in most cases, we administer drugs at sites other than the site of action. Understanding how drugs get to their site of action and how long they stay there is essential to making therapeutic decisions about which drug, what route, how much, how often, and for how long. Classically, how drug moves through the body can be described with ADME, absorption, distribution, metabolism, and elimination. We will highlight the clinically important aspects of each stage of drug movement, as well as demonstrating the effect that differences in these parameters make in drug concentrations. Remember that we most commonly measure the concentrations of drug in the plasma or serum, even though many of our target cells for drug activity are outside the plasma. This is based on the assumption that plasma concentrations correlate with tissue concentrations, so conclusions about tissue concentration can be made from plasma concentrations. This may not be true for all drugs, but it holds true for enough important compounds that it is a reasonable assumption until proven otherwise. Simulated graphs are presented below to demonstrate the effects of changes in pharmacokinetic parameters. These simulations were performed, at the website of David Bourne. AbsorptionAbsorption is usually defined as the proportion of drug moving from the administered drug product into the bloodstream. Drugs administered IV are assumed to be 100% absorbed by definition. For drugs administered PO, major losses of drug occur by not crossing enterocyte membranes in the GI tract, via metabolism in the gut wall (e.g., peptidases), and via metabolism in the liver (since drug absorbed from the GI tract enters portal circulation first and can therefore bring drug into contact with enzymes in hepatocytes before it enters peripheral circulation). Absorption rate can be indicated by the half-life of absorption, sometimes designated as t1/2α. A simulation of serum concentrations is presented in the graph below, in which the only difference between the two lines is a doubling of the absorption rate. This results in a higher Cmax, as well as a shorter time above any given concentration (once absorption is mostly completed). DistributionDistribution refers to the movement of drug from the bloodstream into the interstitial fluid and into other tissues. The mathematical parameter usually used to describe distribution is the volume of distribution (V or Vd or VDss). The volume of distribution can be defined as the apparent volume of fluid needed to contain the total amount of a drug in the body at the same concentration as it is in the plasma. It is an indication of whether drug tends to remain in the vascular system, in total body water, or in tissues. A simulation of serum concentration is shown below, in which the only difference between the two lines is a doubling of the volume of distribution. In this case, a higher volume of distribution results in a lower peak concentration and lower concentrations throughout the time course. MetabolismMetabolism may change pro-drug to active drug, active drug to active metabolite, or active drug to inactive metabolite. A basic understanding of how a drug is metabolized (or if a drug is metabolized) will aid in clinical decision-making in cases in which mechanisms of metabolism are compromised because of disease. Active metabolites should also be considered when examining drug concentration data, since graphs of concentration data may be misleading if they do not contain parent drug and active metabolite. EliminationElimination generally refers to elimination from plasma or serum, and the rate of elimination is designated as ka. Elimination half-life is the time taken for the serum concentration to drop by half, and is often designated as t1/2β. For the most part, it is assumed that the drugs we use regularly for therapeutic purposes follow first order elimination. This means that a constant proportion of drug is removed from the body per unit time. There are some exceptions, in which a constant amount of drug is removed from the body per unit time, designated zero order. Zero order elimination generally occurs when clearance mechanisms have become saturated, so zero order kinetics are more often – Seen with toxic doses of drug. A simulation of serum concentrations in which the elimination rate is doubled is presented below. When elimination rate is increased, overall concentrations are lower as is the peak concentration. A simulation of serum concentrations is presented below, in which the only difference between the lines is a doubling of the dose administered. Careful examination of the graph reveals that the peak concentration in the curve representing the doubled dose is twice that of the lower dose, and the time that concentrations remain above a particular level are moved over one half-life (in this case half-life was set at 1.7 hours). Mathematical DescriptionsTo be complete, we should briefly discuss how pharmacokineticists generate mathematical descriptions of drug movement to allow for predictions and to explain drug behavior and clinical effects. The major methods of mathematical modeling of drug concentration data include compartmental and non-compartment modeling. Compartmental modeling is used to mathematically describe drug movement under particular assumptions about how drugs act; the compartments assumed are not anatomical compartments but rather are artificial methods to describe rates of drug movement. Non-compartmental modeling is based on statistical moment theory, which makes no assumption about how drugs move but rather assumes the drug concentrations at a given time point are independent and can therefore be modeled in a stochastic manner. Regardless of how modeling and mathematically descriptions are performed, the goal is to explain why drug is moving in a particular way and to make predictions about drug movement. ReferencesBrunton, LL, Lazo, JS, and Parker, KL, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 11th edition, McGraw-Hill, 2006 |
What is the process that occurs between the time a drug enters the body and the time it enters the bloodstream?
Postagens relacionadas
direito autoral © 2024 estudarpara Inc.
