Pharmacokinetics is defined as what the body does to the drug and is described by four key stages: Absorption, Distribution, Metabolism and Excretion – often referred to as ADME. This article focuses on the first stage (absorption) and explores how drugs enter the bloodstream, the routes of administration and factors that influence uptake. Absorption Absorption is the process whereby the drug is administered and subsequently enters the bloodstream. Unless given by the intravenous (IV) route, drugs must cross several semi-permeable cell membranes prior to reaching the systemic circulation. Absorption via the enteral route Enteral medications pass through the digestive system (rather than through veins, as in the parenteral route). The most common method is oral administration. Oral dosage forms administered reach the stomach first. Some drugs are unable to survive the acidic environment of the stomach (e.g. insulin) and must therefore be administered by alternative routes. Once the drug passes through the stomach it reaches the small intestine, where drugs are predominantly absorbed. The small intestine has a large surface area, (due to villi and microvilli) and its membranes are more permeable compared to the stomach, making it an ideal site for drug absorption. The absorption of oral formulations depends on several key factors; drug formulation patient characteristics physicochemical characteristics of the drug, the first pass effect These factors are discussed below. Drug formulation Drug formulation affects absorption, For absorption across the gastrointestinal (GI) mucosa, drugs need to be in solution. Therefore oral solid dosage forms such as tablets must undergo disintegration and dissolution prior to absorption. Liquid formulations bypass this step and may be absorbed more rapidly. Some formulations also have special release properties which will affect the rate of absorption and/or where the drug is released in the GI tract: Extended/sustained/prolonged-release forms provide a controlled dose over a period of time (e.g. metformin prolonged release tablets) Delayed-release forms deliver a drug after a delay (e.g. enteric coated drugs). This may be in order to protect the drug from the stomach acid (e.g. pancreatic enzyme replacement therapy), or the stomach from irritation (e.g. aspirin enteric-coated drugs). Often the drug is released in the small intestine via a pH dependent mechanism. Patient characteristics Patient characteristics also affect drug absorption. Patients who have undergone surgical resection of the GI tract may have altered absorption of oral medications. Altered transit time through the GI tract also affects absorption Diarrhoea → faster transit → reduced absorption Food (especially fatty food) → slower gastric emptying time → delayed absorption Physicochemical characteristics Physicochemical characteristics of oral drug formulations such as solubility and permeability infleunce drug absorption. The biopharmaceutics classification system (BCS) classifies drugs in categories I-IV depending on these characteristics. High solubility Low solubility High permeability Class I Class II Low permeability Class III Class IV Class I are likely to have good absorption as they are readily able to disintegrate and dissolve to form a solution (high solubility), then cross the intestinal wall membrane (high permeability). According to BCS, a drug has a high permeability if bioavailability is ≥85% The pKa of a drug will also affect its absorption Drugs in the unionised form are more lipophilic and can cross cell membranes more readily The pKa is a measure of the acidity or basicity of a drug molecule, and is the pH at which concentrations of ionised and unionised forms are equal. If pH < pKa: unionised form of weak acids predominates & ionised form of weak bases predominates Examples: At low pH (stomach ~ 1.4), weak acids are unionised, favouring diffusion through the gastric mucosa At higher pH values (jejunum pH ~ 7-9), weakly basic drugs are unionised, favouring diffusion in the small intestine Aspirin (pKa 4.4): mostly unionised in the stomach favouring drug absorption. However, as the stomach has a smaller surface area and the membrane is less permeable, more aspirin is actually absorbed in the small intestine, even where the pH > pKa. First pass effect After crossing the intestinal mucosa, a drug enters the portal circulation and passes through the liver, where it may undergo metabolism to form inactive metabolites before reaching systemic circulation. This first-pass metabolism reduces the amount of active drug available at the site of action, thereby lowering bioavailability. The bioavailability (F) of a drug is the ratio of the amount of drug reaching systemic circulation to the amount of drug present if the drug had been given via the IV route. Drugs with minimal first pass effect have high oral bioavailability such as clindamycin (F>90%) Drugs with extensive first pass effect have lower bioavailability such as Morphine (F~ 25%) Other routes of absorption Oral cavity (sublingual/buccal): Drugs can also be administered sublingually (under the tongue) or buccally (between the gum and cheek) and are absorbed from the oral cavity straight into the bloodstream. These routes of administration have rapid absorption, bypass pass first metabolism and are useful in swallowing difficulties. However, they are suitable only for lipophilic and low to medium molecular weight drugs, and can only deliver small doses. Rectal (PR): absorbed by the rectum’s blood vessels and flow into the body’s circulatory system and/or act topically at the site. The rectum is a highly vascularised site which makes it an advantageous area for drug delivery, and drugs administered this way partially bypass the first pass effect. This route is limited by poor acceptability. Formulations available include suppositories and enemas. This route is advantageous in swallowing difficulties, in emergency situations (e.g. diazepam for seizures) and where a local effect is advantageous (e.g. mesalazine for ulcerative colitis). Parenteral (IV, SC, IM, Intradermal): Parenteral administration refers to medications placed into the tissues and the circulatory system by injection. Drugs can be given parenterally via the intravenous (IV), subcutaneous (SC), intramuscular (IM) or subdermal routes. Adobe Stock Fig 1. Injection methods These routes are advantageous as they bypass the first pass effect and the GI tract. IV administration provides rapid onset of action and 100% bioavailability, but is invasive, costly and carries infection risk. Subcutaneous (SC) or intramuscular (IM) administration can be painful and only small volumes can be administered, which restricts choice of drug that can be administered. Intradermal administration is uncommon and is often used for allergy tests. Topical: Topical administration means application to body surfaces such as skin or mucous membranes. Can provide a local or systemic effect depending on formulation. Includes transdermal patches, creams/ointments, eye drops, ear drops, nasal sprays, and vaginal preparations. Advantages include bypassing the first pass effect. Disadvantages include skin irritation and limitations on the dose and drug available for delivery. Transdermal Active ingredients delivered across the skin for systemic distribution (e.g. buprenorphine transdermal patches for pain relief) Slow and controlled absorption, convenient and painless for the patient. Only suitable for highly lipophilic drugs and only small doses can be delivered. Creams and ointments Can provide a local effect (e.g. hydrocortisone cream for treatment of eczema) or systemic effect (e.g. testosterone gel for replacement of testosterone). Local effect is advantageous for skin conditions, as well possessing the same benefits and disadvantages described with transdermal delivery of drugs. Summary table The following table summarises common formulations, drug examples, disadvantages and advantages for each route of administration available. Route of administration Formulation Example Advantages Disadvantages Oral (PO) Tablets/Capsules/Orodispersible/solution/suspension Ramipril tablets ✔ Cheap ✔ Readily available ✔ Acceptable for patients ✔ Convenient ✘ Exposed to first pass effect ✘ Tablets and capsules need to go through dissolution step prior to absorption ✘ Variable absorption Oral cavity: Sublingual (SL)/ Buccal Sublingual or buccal formulations Buccastem tablets ✔ No first pass effect ✔ Quick onset of action ✔ Useful for swallowing difficulties ✘ Requires a low-medium molecular weight and lipophilic molecule to be absorbed via oral cavity – not possible for all drugs Intravenous (IV) Solution for IV administration IV Meropenem ✔ Fast onset of action ✔ 100% bioavailability ✔ No first pass effect ✘ Requires intravenous access – chance of infection ✘ More expensive Subcutaneous (SC) Solution for SC administration SC Cyclizine ✔ 100% bioavailability ✔ No first pass effect ✔ Slow controlled absorption ✘ Only small volumes can be administered ✘ Painful ✘ Needle phobic patients may not accept Intramuscular (IM) Solution for IM administration VItamin B12 Transdermal Patch Buprenorphine patch ✔ Slow release of drug possible for patches using reservoir formulations ✔ No first pass effect ✘ Requires a lipophilic molecule to be absorbed transdermally into system circulation ✘ Only suitable for small quantities of drug Topical Cream/ointment/gel Hydrocortisone cream ✔ Reduction of side effects when using for local action e.g. hydrocortisone cream for treatment of eczema ✘ time consuming to apply ✘ contact dermatitis ✘ complex regimens Inhalation Dry powder inhaler or pressurised metered dose inhaler Fostair ✔ Local action so less side effects ✔ No first pass effect ✘ Patient counselling required ✘ Risk of error in administration leading to reduced effectiveness Rectal (PR) Suppository Pentasa Suppository ✔ Local action possible e.g. for ulcerative colitis or haemorrhoids ✔ Highly vascular area increases absorption ✔ Partially avoids first pass effect ✔ Useful in emergencies ✔ Drug can be absorbed into systemic circulation ✘ Poor patient acceptability in UK Vaginal Pessary Clotrimazole pessary ✔ Local action possible e.g. clotrimazole for thrush ✔ No first pass effect ✘ Only possible for people with female genitalia Other: Ocular/Nasal Eye drop/Nasal spray/ Beclomethasone nasal spray ✔ Most commonly used for local treatment which reduces chance of systemic side effects ✔ Nasal: drug can be absorbed into systemic circulation ✘ Dose is limited due to small area for absorption ✘ Route not available for all drugs References Spc Clindamycin 150 mg Capsules Last updated on emc: 14 May 2024 Accessed 11/8/2024 Clindamycin 150 mg Capsules – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) SPC Morphine sulfate 10mg/5ml Oral solution. Last updated on emc: 17 Oct 2023. accessed 11/8/2024 from: Morphine Sulfate 10mg/5ml Oral Solution – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) ICH M9 guideline on biopharmaceutics classification system-based biowaivers. 10 Feb 2020. Available from: M9 Step 5 on biopharmaceutics classification system based biowaivers (europa.eu), accessed 11/8/2024 SPC Pentasa Suppositories 1g – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 3/9/24 SPC NALOXONE 400 microgram/ml solution for injection or infusion – Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk) accessed 5/9/24 Do you think you’re ready? Take the quiz below Pro Feature - Quiz Pharmacokinetics Part 1 – Absorption (ADME) Question 1 of 3 Submitting... 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