Drug Distribution in Bodily Fluids PDF

Drug Distribution in bodily fluid compartments By Rida Jamil  Distribution of drugs in bodily fluid compartments 4 main compartments: intracellular, extracellular, transcellular and intravascular Water comprises 50% to 70% of body weight with variations betwee...

Drug Distribution in bodily fluid compartments By Rida Jamil  Distribution of drugs in bodily fluid compartments 4 main compartments: intracellular, extracellular, transcellular and intravascular Water comprises 50% to 70% of body weight with variations between genders Extracellular fluid holds: Blood plasma (about 4.5% of body weight), interstitial fluid (16%) and lymph (1.2%) Intracellular fluid constitutes 30-40% of body water Transcellular fluid (2.5%) encompasses various specialised compartments such as cerebrospinal, intraocular, peritoneal, pleural, synovial fluids, and digestive secretions Drug distribution within aqueous compartments: Drug exist in both free and bound forms within compartments Weak acids or bases exist as an equilibrium mixture of charged and uncharged forms, influenced by fluid pH and drug pK The blood brain barrier BBB concept: Introduced by Paul Ehrlich to explain dye’s inability to stain the brain after intravenous injection Consists of continuous endothelial cell layer with tight junctions, surrounded by pericytes Efflux pumps extrude substrate molecules, including water-soluble drugs, limiting access to the CNS Limitations: Many drugs with low lipid solubility cannot penetrate Efforts to enhance CNS pharmacotherapy involve modulating permeability proteins Disruption of BBB: Inflammation can disrupt integrity and activity of efflux pumps Intravenous penicillin is preferred over intrathecal administration in bacterial meningitis with intense inflammation Drug examples: Loperamide crosses but rapidly pumps out, confining its effect to the periphery Methylnaltrexone bromide, naloxegol, naldemedine & alvimopan are peripherally acting u-opioid receptor antagonists with limited GI absorption and no CNS penetration Peptides like bradykinin increase BBB permeability Enhancing BBB penetration for anticancer drugs, yet routine clinical application remains elusive despite ongoing effects  Volume of distribution Apparent volume of distribution: defined as the volume that would contain the total body content of the drug (Q) at a concentration equal to that present in the plasma (Cp) Mathematically represented as Vd = Q/Cp Avoid close identification of Vd with a specific anatomical compartment Drugs may exert at low concentrations accessing their receptors Example with insulin: Insulin’s Vd is like plasma water volume Exerts effects on muscle, fat, and liver cells via receptors exposed to the interstitial fluid, not plasma  Drugs confined in the plasma compartment Plasma volume is approx. 0.05 L/Kg of body weight Drugs confined to plasma: Some drugs like heparin are confined to plasma due to their large molecular size Retention in plasma after a single dose often results from strong binding to plasma proteins Pharmacological effects: Despite plasma binding, free drug in interstitial fluid exerts pharmacological effects With repeated dosing, equilibrium occurs leading to an increase in measured Vd Some dyes, like Evan’s blue bind strongly to plasma albumin, and it’s Vd has been used experimentally to measure plasma volume Class 1 and 2 drugs causes drug-drug interaction in plasma albumin. It can be divided into 2 classes, depending on the dose of the drug being > or < than the binding capacity of albumin Class 1 drugs: Dose of the drug < than the binding capacity of plasma albumin, dose/capacity ratio is low as most drugs are bound to albumin and the free drug is low, meaning binding sites of drug are in excess and fraction of the drug bound is high Class 2 drugs: Dose of the drug > than the binding capacity of plasma albumin, dose/capacity ratio is high as most drug molecules are bound to albumin and the free drug is significant, meaning that dose is greater than available Drugs confined in the extracellular compartment Total extracellular volume is approx. 0.2 L/Kg of body weight Vd for polar compounds: Many polar compounds, such as vecuronium, gentamycin & carbenicillin has Vd close to the extracellular volume These compounds have low lipid solubility, making it difficult for them to enter cells Polar compounds do not freely transverse the BBB or placenta barriers Macromolecular biopharmaceuticals: Notably monoclonal antibodies distribute in the extracellular space and access receptors on cell surfaces but do not readily penetrate cells Nucleic acid-based biopharmaceuticals: Act intracellularly and often require special delivery systems to facilitate access to the cell interior  Drugs confined to the total body compartment Represents approx. 0.55 L/Kg Many drugs that readily cross the cell membranes, like phenytoin and ethanol, have a Vd close to total body water volume Factors increasing Vd: Drug binding outside the plasma compartment Partitioning into body fat What drugs exceed the total body volume? Morphine, TCA’s and Haloperidol How are drugs removed when they are greater than total body volume? Haemodialysis filters blood plasma, making it unhelpful in managing overdose with such agents Not removed efficiently by haemodialysis  Drug interactions caused by altered absorption? Gastrointestinal absorption modulation: Slowed by drugs inhibiting gastric emptying like atropine or opiates Accelerated by drugs hastening gastric emptying (e.g. metoclopramide) Interactions affecting absorption: Example: Ca2+ and Fe2+ from insoluble complexes with tetracycline, retarding absorption; colestyramine binds drugs like warfarin and digoxin, preventing their absorption when administered close together Physiological effects on absorption: Adrenaline added to local anaesthetic injections causes vasoconstriction, slowing anaesthetic absorption and prolonging its local effect. Physiological based modelling: Emerging use in predicting effects of genetic polymorphisms of drug transporters in the intestine and hepatocytes Also predict drug-drug interactions due to competition for these transporters  Drug interactions through alteration of distribution Drugs may compete for a common binding site on plasma albumin or tissue protein, but clinical significance is rare unless accompanied by an effect on drug elimination Displacement of drugs from binding sites transiently increases free drug concentration, followed by increased elimination, resulting in a new steady state with reduced total drug concentration but similar free drug concentration (class 1 and 2 drugs) Consequences of clinical importance: Increase in free drug concentration causes harm before reaching new steady state Dose adjustments based on total plasma concentration may need revision due to altered therapeutic range by co-administration of a displacing drug Severe toxicity may happen if displacing drug reduces elimination of the first drug, leading to chronic increase in free concentration at the new steady state Examples: Protein-bound drugs acting as displacing agents include sulphonamides, choral hydrate and its metabolite trichloroacetic acid Displacement of bilirubin from albumin in jaundiced premature neonates can lead to kernicterus, causing permanent movement disturbances Phenytoin dose adjustments based on total plasma concentration may lead to increased dose prescription and harm if therapeutic range reduction due to displacing drug interaction is not recognised Drugs altering protein binding may also reduce elimination of the displace drug, leading to severe interactions (e.g. salicylates & methotrexate, quinidine, verapamil, amiodarone with digoxin.  Altered distribution because of competition for shared transporters Drug competition between transporters: Carrier-mediated transport by SLC (solute carrier) and ABC (ATP-binding cassette) mechanisms involved in drug distribution, absorption, excretion and access to metabolising enzymes in the liver Examples: Organic anion transporter (OAT) excluding penicillin from the CNS Implications of transporter mediated processes: Crucial for drug distribution, absorption, excretion and metabolism Transporter-mediated drug-drug interactions of significant interest New approaches for predicting transporter-mediated interactions: Interest utilizing endogenous substrates as biomarkers for transporter function These approaches aim to enhance prediction accuracy and improve understanding of drug interactions involving transport mechanisms Special Drug Delivery Systems Pro-drugs Antibody-drug conjugates Packaging in liposomes Coated implantable devices Pro-drugs They are inactive precursors metabolised to active metabolites Some examples: Cyclophosphamide can be taken orally without GI damage Levodopa crosses the BBB and converts to active dopamine Zidovudine confers selectivity toxicity towards HIV-infected cells Valaciclovir and famciclovir have greater bioavailability than their active metabolites acyclovir and penciclovir Diacetyl morphine (Heroin) penetrates the BBB faster than its active metabolites, enhancing abuse potential Delivering nucleic acid-based drugs: Major issue due to intracellular site of action Conjugation with N-acetylgalactosamine (GalNAc) permits drug delivery to hepatocytes via asialoglycoprotein receptor (ASGR) Overcoming other problems with pro-drugs: Instability at gastric pH, gastric irritation, inability to cross the BBB etc. Aspirin was intentionally synthesised as a pro-drug of salicylic acid to enhance tolerability when taken orally Successes in delivering nucleic acid drugs back to hepatocytes highlight potential of pro-drug strategies  Antibody drug conjugates Aim of cancer chemotherapy: Improve selectivity of cytotoxic drugs Approach: Attach drug or toxin to an antibody directed against a tumour-specific antigen for selective binding to tumour cells Result: Surge of licensed agents, including 12 currently licensed by the FDA Examples: Ado-trastuzumab emtansine: Trastuzumab (HER-2 targeted antibody) complexed with microtubule inhibitor DM1 via a linker molecule Used for HER-2 positive metastatic breast cancer Trastuzumab inhibits HER-2 receptor signalling and delivers DM1 to tumour site Improved progression-free and overall survival demonstrated in clinical trials Brentuximab vedotin: Antibody-drug conjugate targeting CD-30 antigen, used for selected lymphomas Gentuzumab ozogamicin: CD33 mAb-cytotoxic agent conjugate targeting myeloid progenitor cells, used for CD33-positive relapsed or refactory acute myeloid leukemia Reintroduced into clinic after addressing earlier safety concerns  Packaging in liposomes Liposomes: Vesicles 0.1-1 um in diameter formed by sonication of an aqueous suspension of phospholipids Can encapsulate non-lipid soluble drugs, retaining them until liposome disruption Taken up by the reticuloendothelial cells, especially in the liver Concentrated in malignant tumours Commercially available: Amphotericin: Available in less nephrotoxin and better tolerated liposomal formulation for treating systemic myocytes Long-acting form of doxorubicin encapsulated in liposomes: used for treating malignancies like ovarian cancer and myeloma Paclitaxel: available in an albumin nanoparticle preparation for breast cancer treatment Liposomal cytarabine: Available for intrathecal treatment of lymphomatous meningitis Liposomal vincristine: Available for selected patients with acute lymphoblastic leukaemia  Coated implantable devices Impregnated coatings for localised drug delivery from implants: Examples – Hormonal delivery to the endometrium from intrauterine devices Depo-Provera subcutaneous protection Delivery of antithrombic and antiproliferative agents to coronary arteries from stents Stents: Expansile tubular devices inserted via catheter after dilating coronary artery with a ballon Reduce occurrence of re-stenosis, but it can still occur at the margin of the device Coating stents with drug like sirolimus: Sirolimus is a potent immunosuppressant Embedded in a surface polymer to prevent re-stenosis Prevents an important clinical problem associated with stents