Drug Testing Locations - Devon Berwyn, PA

Drug Testing in Devon Berwyn, PA

Devon Berwyn, Pennsylvania Statistics

How does the body eliminate Drugs

Drug elimination is the sum of the processes of removing an administered drug from the body. In the pharmacokinetic ADME scheme (absorption, distribution, metabolism, and excretion), it is frequently considered to encompass both metabolism and excretion. Hydrophobic drugs, to be excreted, must undergo metabolic modification making them more polar. Hydrophilic drugs, on the other hand, can undergo excretion directly, without the need for metabolic changes to their molecular structures.

Although many sites of metabolism and excretion exist, the chief organ of metabolism is the liver, while the organ primarily tasked with excretion is the kidney. Any significant dysfunction in either organ can result in the accumulation of the drug or its metabolites in toxic concentrations.

A variety of other factors impact elimination — intrinsic drug properties, such as polarity, size, or pKa. Also other factors include genetic variation among individuals, disease states affecting other organs, and pathways involved in the way the drug distributes through the body, such as first-pass metabolism.

Issues of Concern

Drug elimination is the removal of an administered drug from the body. It is accomplished in two ways, either by excretion of an unmetabolized drug in its intact form or by metabolic biotransformation followed by excretion. While excretion is primarily carried out by the kidneys, other organ systems are involved as well. Similarly, the liver is the primary site of biotransformation, yet extrahepatic metabolism takes place in a variety of organ systems affecting multiple drugs.

Given the multiple organ systems and the variety of metabolic transformations present, drug elimination can entail a significant degree of complexity. Hydrophilic drugs are typically directly excreted by the kidneys, while hydrophobic drugs undergo biotransformation before excretion. The purpose here is twofold – biotransformation serves both detoxify the exogenous substances as well as to increase their hydrophilicity, ensuring their elimination via the kidneys.

Two broad metabolic pathways of hepatic drug transformation exist. Phase I is the direct modification of the target molecule, whereas phase II entails conjugation of the target to a polar molecule of low molecular weight. Phase I prepare the drug to enter phase II, but single-phase metabolism also exists.

Phase I involves oxidation, reduction, and hydrolysis of the exogenous molecule. These reactions are accomplished by hepatic microsomal enzymes, which reside in the smooth endoplasmic reticulum of the hepatocytes. Best known among them is the cytochrome P450 system, whose enzymes are predominantly involved in oxidative metabolism. Within the cytochrome P450 family (CYP), the enzyme responsible for the metabolism of more than 50% of existing drugs is the CYP3A4. Its activity encompasses various classes of medications, including opioids, immunosuppressants, antihistamines, and benzodiazepines. The enzymes can also be induced or inhibited by a variety of substances they interact with, including pharmaceuticals. The increase in metabolic activity with CYP induction results in a diminished activity of drugs targeted by that particular isoform. Conversely, CYP inhibition will result in increased drug plasma concentration, potentially leading toxicity. The CYP3A4 is induced by phenytoin, phenobarbital, and St. John's wort, while diltiazem, erythromycin, and grapefruit inhibit it. Caution is, therefore, necessary when administering CYP3A4-metabolized drugs in the presence of any of the inhibitors or inducers.

Phase II consists of covalent bonding of polar groups to nonpolar molecules to render them water-soluble and allow renal or biliary excretion. Target molecules enter phase II directly or via initial processing through phase I. A variety of polar adjuncts is transferred, including amino acids, glucuronic acid, glutathione, acetate, and sulfate. Glucuronidation is one of the major pathways of phase II biotransformation. The UDP-glucuronosyltransferase (UGT) enzyme family performs this activity. Typically, glucuronide derivatives possess less or no activity of the original drug, but in some cases, pharmacologically active compounds result. Morphine-6-glucuronide is a phase II metabolite of morphine with significant analgesic activity. As with the CYP enzymes, inducers, and inhibitors of phase II, enzymes exist and may influence the efficacy of drugs that rely on conjugation before excretion.

The first-pass effect is a feature of hepatic metabolism that also plays a role in the elimination of multiple drugs. Here, the enteric consumed drugs are exposed directly to the liver via the portal vein, where they undergo biotransformation before entering the systemic circulation. This activity reduces the bioavailability and needs to be factored into the dose administered to the patient. Intravenously administered drugs are not subject to the first-pass effect.

Extrahepatic drug metabolism takes place in the GI tract, kidneys, lungs, plasma, and skin.

Renal excretion completes the process of elimination that begins in the liver. Polar drugs or their metabolites get filtered in the kidneys and typically do not undergo reabsorption. They subsequently get excreted in the urine. Urinary pH has a significant impact on excretion, as drug ionization changes depending on the alkaline or acidic environment. Increased excretion occurs with weakly acidic drugs in basic urine and weakly basic drugs in acidic urine.

Excretion in the bile is another significant form of drug elimination. The liver can actively secrete ionized drugs with a molecular weight greater than 300 g/mol into bile, from where they reach the digestive tract and are either eliminated in feces or reabsorbed as part of the enterohepatic cycle.

Other pathways of excretion include the lungs, breast milk, sweat, saliva, and tears

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