Distribution Biopharmaceutics Pdf

[Leto Corrales]

Pharmacokineticsfocuses on drug movement throughout the human body via the processes of absorption, distribution, and elimination. Upon administration, a drug moves from the site of administration and gets absorbed into the systemic circulation where it will then gets distributed throughout the body. The process of distribution refers to the movement of a drug between the intravascular (blood/plasma) and extravascular (intracellular & extracellular) compartments of the body. Within each compartment of the body, a drug exists in equilibrium between a protein-bound or free form. Over time, drugs within the circulation will then be metabolized and excreted from the body by the liver & kidneys.[1][3]

Drugs that display single compartment distribution kinetics with a straight line graph on plasma vs. time curves. Because the drug is said to distribute instantaneously, the initial plasma concentration of drug at time = 0 (Co) is difficult to measure and is therefore estimated via extrapolation to time = 0 on a plasma concentration vs. time curve.[1][2][3]

Half-life (t1/2) refers to the time required for plasma concentration of a drug to decrease by 50%. t1/2 is dependent on the rate constant (k), which is related to Vd & clearance (CL).[1][2][3] Half-life can be expressed using the following equation(s):

Only the drug located in the central compartment can be eliminated from the body because the process of elimination is primarily carried out by the liver and kidneys. Drugs with a high Vd will have a large fraction of drug remaining outside of the central compartment. Meanwhile, the fraction of drug in the plasma will be eliminated, causing a shift of equilibrium resulting in drug located in the peripheral compartment to shift into the central compartment. This shift will cause the plasma concentration to remain at a steady-state concentration despite drug removal from the body. This phenomenon causes plasma concentration to decline more slowly during the elimination phase in the setting of a high Vd.[1][3]

As previously discussed, multiple values of Vd can be calculated depending on the intrinsic drug kinetics (single vs. multiple compartment models) as well as the phase of drug kinetics following drug administration (distribution phase vs steady state vs terminal elimination phase). However, from the clinical perspective, the single most important utility of Vd is calculating the loading dose of a drug.[1][3]

The loading dose is best calculated using the Vd at steady state (Vss) as it is the most representative of the specific drugs pharmacokinetic properties at desired steady-state plasma concentration. Therefore, the loading dose can be calculated using the following equation:

After administration of a loading dose, additional maintenance doses can be administered to maintain the desired plasma concentration of the drug. Unlike, the loading dose, which is dependent on the drug's Vd, the maintenance dose is dependent on clearance (Cl).[3] Maintenance dosing can be calculated with the following equation:

Understanding volume of distribution is important for both physicians and pharmacologist who prescribe and dose medications. Differentiating pharmacologic agents who have high versus low volume of distributions is essential in appropriately dosing medications for patients. While physicians generally dose medications in low complexity cases, patients in the intensive care unit might need their medications dosed by a pharmacist. Understanding and calculating different models of distribution, the factors that can affect the volume of distribution, loading dose, and maintenance doses can mean the difference between life and death. When dosing medication, it is of the utmost importance to promptly consult an interprofessional group of specialists.

Pharmacokinetics is the study of a drug moiety or a compound as it moves through the body after its administration. It involves the processes of drug absorption, bioavailability, clearance, and distribution.[1] Although these processes are theoretically separate, from a practical standpoint in-vivo, they are all inter-connected. After the drug is absorbed from the site of administration, it is distributed to extracellular fluids.[2] High reserves of plasma protein-bound drugs can cause prolonged effects by creating a sustained release mechanism.[3]

Drug distribution is impacted by several factors related to the drug and the body. The drug-related factors include blood and tissue binding proteins, pH, and perfusion. The body-related factors include body water composition, fat composition, diseases (e.g., volume depletion, burns, third spacing).

As people age, the overall body water reduces. However, intracellular water remains relatively stable from the first month of life to adulthood. Higher doses of drugs per kilogram weight are required in younger children as they have a higher percentage of water.[5] Lipophilic drugs are more likely to distribute to areas of high lipid density.[6] Body fat varies with age, gender and genetics. Many drugs are bound to plasma proteins, and the most important drug-binding proteins include albumin and globulins. The concentration of these proteins varies with age, nutritional status, and disease.

Understanding drug distribution and pharmacokinetics (PK) is important for all clinicians prescribing medication, along with understanding the fundamentals of protein binding.[7] Only free and unbound drugs will pass from vascular spaces to tissues where a drug-receptor interaction will occur as well as the effect of the drug. Protein binding is not only affected by the concentration of protein but also the pH, metabolic abnormalities (hyperglycemia, uremia), and the presence of other chemicals that will compete for protein binding.

Competition for plasma binding can influence drug effects. For example, Aspirin and Warfarin are known to compete for the same plasma protein binding site. Administering both drugs at the same time will increase the unbound drug, thereby potentiating their effects and potentially lead to bleeding risk.[8] For a drug to be effectively eliminated by the kidney, the drug must be metabolized from a lipophilic molecule into a polar molecule. The liver produces a polar metabolite of the drug, using two unique sets of reactions known as phase I metabolism and phase II metabolism.[9]

Phase I metabolism involves what is known as the cytochrome P-450 system (CYP enzyme). CYP alters a drug in such a way so that it will be more amenable to combining with polar molecules. These reactions involve basic chemistry principles such as oxidation, reduction, or hydrolysis. Phase II metabolism is the process of adding a polar moiety to the drug, such as sulfate, acetate, or glucuronate. The addition of a polar moiety to a drug makes the drug water-soluble and available for excretion by the kidney.

Additionally, uremia not only affects protein binding, but kidneys also play a significant role in drug absorption, distribution, metabolism, and excretion (ADME). Renal dose adjustment is essential in moderate to severe renal failure. Important strategies for managing and drug dosing must be adjusted accordingly, and the risks must be weighed against the benefits.[10]

Several factors impact drug distribution. These factors include the concentration of drug transporters in blood, pH, perfusion, body water composition, body fat composition, and most certainly disease conditions (e.g., volume depletion, burns, third spacing). The majority of protein binding is relevant only when the drug is more than 90 percent protein bound. In the hypoalbuminemia state, which occurs in malnutrition and inflammation, there is a higher concentration of the unbound drugs. Body composition and metabolic factors also affect drug distribution. For example, during the last trimester of pregnancy, plasma volume expands, so there is an overall diluting effect on plasma proteins. There is also a change in adipose tissue. Additionally, pregnant women are frequently excluded in clinical trials related to drugs.[11] In a critically ill patient, drug distribution also changes due to deranged physiology, protein binding changes, fluid shifts, pH changes, and vascular organ perfusion.[12] Thus it could be useful to monitor drug levels in these conditions if possible.

The interprofessional team and healthcare professionals, including laboratory technologists, pharmacists, nurses, and clinicians, need to all work together to ensure the safety and efficacy of administered drugs. After the clinician chooses the choice and dosage of a particular drug, the pharmacist should verify dosing, report any drug interactions, and take notice of special clinical situations that will influence drug levels and hence efficacy as well as adverse events (e.g., albumin levels, changes in weight, malnutrition, renal and hepatic function). In one study in chronic kidney disease patients, pharmacists identified 5302 drug-related problems and made 3160 recommendations with acceptance rates up to 95%.[15]

When possible and indicated plasma levels should be followed. Nurses play a critical role in drug administration and alerting the team regarding errors related to medication reconciliation.[16] This team collaboration is an essential part of patient safety in the inpatient and outpatient setting.

The volume of the compartment, the volume of distribution (Vd), is defined as the ratio between the total amount of chemical present in the compartment at a given time, A(t), and the concentration at a specific site at the same time, C(t):

In practice, the volume of distribution can be determined as follows. The chemical is given as a bolus dose (D), for example, an intravenous injection, at time zero. Thus, at time zero the amount of chemical in the body (A0) is equal to the dose, provided that the availability is 100%. The concentration of the chemical is measured in blood or plasma. Since distribution is not immediate, the concentration at time zero cannot be determined accurately. Therefore, the concentrations in several samples obtained at different times after dosing are plotted and the concentration at time zero (C0) is estimated by back extrapolation (Fig. 2). The volume (Vd) is then calculated as

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