II. Definitions
- Pharmacokinetics (or kinetics)
- Absorption, Distribution, Metabolism and Excretion (ADME)
- Biological Availability (Bioavailability)
- Rate and amount of drug absorption into the bloodstream and distribution to tissues
- Measured by serum concentrations or by pharmacologic or therapeutic response
- Metabolic Clearance Rate
- Rate that a drug and its metabolites are cleared from tissue and body fluids
- Drug elimination is chiefly via renal and Hepatic Clearance
- Renal Elimination
- Drug clearance via the Kidney and urine
- Hepatic Elimination
- Drug clearance via the liver, biliary tract and intestinal tract
- First Pass Effect (First Pass Metabolism)
- Drugs taken orally must first pass through the liver where they may be metabolized to inactive forms (reducing their Bioavailability)
- Half-Life (T1/2)
- Time required for a drug's plasma concentration to drop 50% after discontinuation
- Distribution Half Life (T1/2a)
- Time required for a drug's plasma concentration to drop 50% as it distributes to body tissues (typically rapid over minutes)
- Elimination Half-Life (T1/2b)
- Time required for half of a drug to be metabolized and excreted (typically slow over hours)
- Steady State
- Plasma concentration that is consistent (continuous IV infusion) or fluctuating in a consistent range (intermittent dosing)
- Drugs reach their steady state (plasma concentration, peak or trough) typically after 4-5 drug half-lives
III. Types: Proteins that increase drug water solubility and in turn aid elimination
- Cytochrome P450
- Uridine Diphosphate-glucuronosyltransferase (UGT) Conjugating Enzyme
- Glucuronosyltransferases perform Glucuronidation primarily in the liver and aid drug excretion
IV. Types: Transport Proteins move drugs and metabolites from one body compartment to another
-
Adenosine Triphosphate binding casette (ABC) drug uptake/efflux transporters
- Enzymes: Efflux pump P-Glycoprotein (P-gp)
- Organic anion-transporting polypeptide (OATP) drug transporters
- Enzymes: OATP1A1, OATP1A2, OATP2B1
V. Dosing
- Single dose
- Drug reaches a peak plasma concentration after full absorption or infusion
- Plasma levels typically fall at a consistent linear rate as tissue distribution, metabolism and excretion occur
- Continuous IV infusion
- Drugs reach their steady state plasma concentration after 4-5 drug half-lives
- Increased infusion rate raises the plasma concentration but does not decrease the time to steady state
- Intermittent dosing
- Drugs reach their steady state (fluctuation between consistent peak or trough) typically after 4-5 drug half-lives
- Peak
- High point of drug plasma concentration
- Drug toxicity is more likely to occur at peak drug concentration
- Trough
- Low point of drug plasma concentration
- Inadequate drug effect is more likely to occur at trough concentration
- Loading dose
- Drug loading doses (higher initial dose or doses) may be given to reach higher early therapeutic peak plasma concentrations
- Subsequent maintenance doses follow loading doses
- Time to steady state is not affected by the loading dose, and still depends solely on drug Half-Life
- Onset of Drug Activity
- Onset of therapeutic drug effect
- Primarily affected by Drug Administration Route (e.g. slow via oral route, rapid via IV)
- Duration of Drug Activity
- Duration of therapeutic drug effect
- Most influenced by a drug's Half-Life, although other factors (e.g. prolonged receptor binding) may extend activity duration
VI. Physiology: Pharmacokinetics
- Absorption
- Bioavailability of a drug is dependent on absorption of that drug across multiple membrane surfaces
- Passive diffusion allows for small, lipophilic, nonionic molecules to rapidly cross membranes, following a concentration gradient
- Facilitated diffusion relies on carrier molecules to cross membranes
- Aqueous channels allow small (MW <200), hydrophilic molecules to cross membranes, following a concentration gradient
- Active transport requires both a carrier molecule (facilitated) and ATP for specific drugs to cross membranes, against a gradient
- Absorption is dependent on multiple drug characteristics (polarity, size, solubility, formulation)
- Small, nonionized, lipid soluble drugs have the highest absorption (most membrane permeable)
- Patient factors impact absorption (e.g. GI Tract perfusion, Stomach acidity, interacting ingested substances including food)
- Bioavailability of a drug is dependent on absorption of that drug across multiple membrane surfaces
- Distribution
- Apparent Volume of Distribution (Vd)
- Calculated volume needed to contain the total administered drug at the same measured plasma concentration
- Vd indicates the degree of tissue distribution of a drug compared with its plasma distribution (volume of plasma in adults)
- Drugs limited to plasma distribution would have a Vd = 3 Liters
- Drugs limited to extracellular compartment would have a Vd = 16 Liters (plasma and interstitial fluid)
- Drugs with very large Vd (e.g. >46 liters, greater than Total Body Water) suggest a drug depot effect
- Membrane permeability
- Small, lipophilic drugs may rapidly cross intestinal lining, capillary walls and the blood brain barrier
- Other drugs may fail to cross key membranes
- Blood brain Barrier (differentiates drugs with CNS effects)
- Blood-placenta Barrier (differentiates drugs considered safe in pregnancy)
- Blood to Breast Milk Barrier (differentiates drugs considered safe in Lactation)
- Blood-Testes Barrier
- Plasma Protein binding
- Protein-bound drugs (e.g. albumin bound) are typically inactive and not distributed to organs and tissue
- Free drug concentrations are key to the drugs distribution and activity
- Depot Storage
- Lipophilic drugs may accumulate in fat and result in prolonged effects
- Drugs that bind Calcium may accuulate in bone and teeth
- Apparent Volume of Distribution (Vd)
- Metabolism
- Drug Metabolism typically results in a more polar (and more water soluble) drug
- Prodrugs (inactive or less active) must be metabolized to their active drug forms
- Prodrug examples include Clopidogrel, Prednisone, valacylovir
- Many, less polar drugs require metabolism before they are able to be excreted
- Polar drugs (e.g. Gentamicin, Digoxin) do not require metabolism before excretion
- Reaction Phases
- Phase 1 Reaction (non-synthetic)
- See Redox Reaction
- Oxidation or reduction of a drug into a more polar form
- Phase 2 Reaction (synthetic)
- Polar group is conjugated to the drug, resulting in a highly polar agent
- Phase 1 Reaction (non-synthetic)
- Cytochrome P450 System
- Hepatocytes in the liver contain a P450 family of microsomal enzymes on the endoplasmic reticulum
- P450 Enzymes facilitate drug oxidation and reduction, utilizing NADPH donated electrons (Phase 1 Reaction)
- Excretion
- Most drugs (90%) require metabolism to more polar and water soluble agents before excretion
- Majority of drugs are excreted in the urine
- Renal dysfunction may be associated with drug accumulation
- Urine excretion depends on glomerular filtration, tubular secretion and tubular reabsorption
- Glomerular Filtration allows easy passage of small non-ionic drugs, but typically blocks Protein-bound drugs
- Tubular secretion requires active transport of specific drugs competing for carrier binding sites
- Tubular reabsorption is typically of small nonionic drugs, which may result in their lower excretion rates
- Ionic drugs are poorly reabsorbed and typically have higher excretion rates
- Some drugs are excreted in stool (may be concentrated in bile)
- Enterohepatic circulation may result in prolonged drug effects after a drug is reabsorbed after excretion
- Clearance
- Clculated rate that a drug and its metabolites are cleared from tissue and body fluids
- Drug Clearance (L/h) = ElimRate / DrugConc
- Where ElimRate = Elimination Rate (mg/h)
- Where DrugConc = Drug Concentration (mg/L)
- Drug Clearance is measured in L/h (contrast with Rate of Elimination, measured in mg/h)
VII. Physiology: Drug Dependency
- Drug Tolerance
- Drug dosing needs to be increased to maintain the same prior effect
- Mechanisms
- Metabolic (Drug Metabolism is upregulated as dosing is increased)
- Cellular (drug receptors are down regulated)
- Examples: Alcohol Tolerance
- Blood Alcohol Level falls 0.03/h in Alcoholics compared with 0.02/h in others
-
Drug Dependence
- See Chemical Dependence
- Drug is required by patient to maintain normalcy (often with withdrawal symptoms when that drug is stopped)
- Examples: Alcohol Dependence, Benzodiazepine Dependence
-
Drug Withdrawal
- Drug stoppage results in exaggerated symptoms
- Examples: Alcohol Withdrawal, Opioid Withdrawal, Antidepressant Withdrawal
VIII. Physiology: Patient Factors
IX. References
- Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12
- Asher (2017) Am Fam Physician 96(2): 101-7 [PubMed]
Images: Related links to external sites (from Bing)
Related Studies
| adme (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| ADMELOG 100 UNIT/ML VIAL | $9.43 per ml | |
| ADMELOG SOLOSTAR 100 UNIT/ML | $12.13 per ml | |
Ontology: Biological Availability (C0005508)
| Definition (CHV) | the amount of drug that reaches the blood after it has been administered |
| Definition (CHV) | the amount of drug that reaches the blood after it has been administered |
| Definition (NCI) | The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action (21CFR320.1). |
| Definition (MSH) | The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action. |
| Definition (PSY) | The degree and rate at which a drug enters the bloodstream and is circulated to specific organs or tissues, as measured by drug concentrations in body fluids or by pharmacologic or therapeutic response. |
| Concepts | Quantitative Concept (T081) |
| MSH | D001682 |
| English | Availabilities, Biologic, Availabilities, Biological, Availabilities, Physiologic, Availability, Biologic, Availability, Biological, Availability, Physiologic, Bioavailabilities, Bioavailability, Biologic Availabilities, Biologic Availability, Biological Availabilities, Physiologic Availabilities, Physiologic Availability, AVAILABILITY BIOL, AVAILABILITY PHYSIOL, PHYSIOL AVAILABILITY, BIOL AVAILABILITY, bioavailability of drug, drug bioavailability, bioavailability, Biological Availability |
| Swedish | Biologisk tillgänglighet |
| Czech | biologická dostupnost |
| Finnish | Biologinen availabiliteetti |
| French | Disponibilité biologique, Disponibilité physiologique, Biodisponibilité |
| Russian | BIOLOGICHESKAIA USVOIAEMOST', EKVIVALENTNOST' USVOIAEMOSTI, USVOIAEMOST' FIZIOLOGICHESKAIA, BIOUSVOIAEMOST', БИОЛОГИЧЕСКАЯ УСВОЯЕМОСТЬ, БИОУСВОЯЕМОСТЬ, УСВОЯЕМОСТЬ ФИЗИОЛОГИЧЕСКАЯ, ЭКВИВАЛЕНТНОСТЬ УСВОЯЕМОСТИ |
| Japanese | 薬物生体内利用率等価性, 生理的利用率, バイオアベイラビリティ, 生物学的利用率, 生物学的利用能 |
| Croatian | BIOLOŠKA DOSTUPNOST |
| Polish | Dostępność biologiczna, Dostępność fizjologiczna, Równoważnik dostępności, Biodostępność |
| German | Biologische Verfügbarkeit, Bioverfügbarkeit, Physiologische Verfügbarkeit |
| Dutch | Beschikbaarheid, biologische, Biobeschikbaarheid, Biologische beschikbaarheid |
| Portuguese | Biodisponibilidade, Disponibilidade Biológica, Disponibilidade Fisiológica |
| Italian | Biodisponibilità |
| Spanish | Biodisponibilidad, Disponibilidad Biológica, Disponibilidad Fisiológica |
Ontology: Half-Life (C0018517)
| Definition (NCI) | The time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity.(MeSH) |
| Definition (MSH) | The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. |
| Concepts | Temporal Concept (T079) |
| MSH | D006207 |
| English | Half-Life, Half-Lifes, Halflife, Halflifes, Half Life, Half-Life [PK], half lifes, half-life, half life, half-lifes |
| Swedish | Halveringstid |
| Czech | poločas |
| Finnish | Puoliintumisaika |
| Russian | PERIOD POLURASPADA, POLUPERIOD, ПЕРИОД ПОЛУРАСПАДА, ПОЛУПЕРИОД |
| Japanese | 半減期 |
| Polish | Półtrwanie |
| Norwegian | Halveringstid |
| Spanish | Periodo Radiactivo, Vida Media |
| Portuguese | Período Radioativo, Meia-Vida Radioativa, Meia-Vida |
| French | Demi-vie |
| German | Halbwertzeit |
| Italian | Emivita |
| Dutch | Halfwaardetijd, Halveringstijd |
Ontology: Metabolic Clearance Rate (C0025515)
| Definition (CSP) | rate at which a substance (e.g., a drug) is removed from the body. |
| Definition (MSH) | Volume of biological fluid completely cleared of drug metabolites as measured in unit time. Elimination occurs as a result of metabolic processes in the kidney, liver, saliva, sweat, intestine, heart, brain, or other site. |
| Concepts | Clinical Attribute (T201) |
| MSH | D008657 |
| SnomedCT | 28771004 |
| English | Clearance Rate, Metabolic, Clearance Rates, Metabolic, Metabolic Clearance Rate, Metabolic Clearance Rates, Rate, Metabolic Clearance, Rates, Metabolic Clearance, METAB CLEARANCE RATE, Metabolic clearance rate, function, clearance rate, Metabolic clearance rate, Metabolic clearance rate, function (observable entity), Metabolic clearance rate (function) |
| Spanish | velocidad de depuración metabólica, función, velocidad de clearance metabólico, velocidad de depuración metabólica, función (entidad observable), velocidad de depuración metabólica, índice de clearance metabólico, índice de depuración metabólica (entidad observable), índice de depuración metabólica (función), índice de depuración metabólica, Tasa de Depuración Metabólica |
| Swedish | Metabol clearance-hastighet |
| Czech | metabolická clearance |
| Finnish | Metabolinen puhdistumanopeus |
| Russian | METABOLICHESKOGO KLIRENSA SKOROST', МЕТАБОЛИЧЕСКОГО КЛИРЕНСА СКОРОСТЬ |
| French | Clairance, Clairance métabolique |
| Italian | Velocità di clearance metabolica |
| Polish | Wskaźnik klirensu metabolicznego |
| Norwegian | Metabolsk clearancehastighet |
| German | Metabolische Clearance, Metabolische Clearance-Rate |
| Dutch | Klaring, metabole |
| Portuguese | Taxa de Depuração Metabólica |
Ontology: Drug Kinetics (C0031327)
| Definition (CHV) | how a drug is absorbed, distributed, metabolized, and eliminated by the body |
| Definition (CHV) | how a drug is absorbed, distributed, metabolized, and eliminated by the body |
| Definition (NCI_CDISC) | The characteristic movements of drugs within biological systems, as affected by absorption, distribution, binding, elimination, biotransformation, and excretion; particularly the rates of such movements. (NCI) |
| Definition (NCI_NCI-GLOSS) | The activity of drugs in the body over a period of time, including the processes by which drugs are absorbed, distributed in the body, localized in the tissues, and excreted. |
| Definition (NCI) | The characteristic movements of drugs within biological systems, as affected by absorption, distribution, binding, elimination, biotransformation, and excretion; particularly the rates of such movements. |
| Definition (MSH) | Dynamic and kinetic mechanisms of exogenous chemical and DRUG LIBERATION; ABSORPTION; BIOLOGICAL TRANSPORT; TISSUE DISTRIBUTION; BIOTRANSFORMATION; elimination; and DRUG TOXICITY as a function of dosage, and rate of METABOLISM. LADMER, ADME and ADMET are abbreviations for liberation, absorption, distribution, metabolism, elimination, and toxicology. |
| Definition (CSP) | distribution and effectiveness of a drug throughout the body as a function of route, schedule, vehicle, chemical isomer, metabolism, and other factors. |
| Concepts | Physiologic Function (T039) |
| MSH | D010599 |
| English | Drug Kinetics, Kinetics, Drug, Pharmacokinetics, mechanism of action, PHARMACOKIN, PK, drug kinetics, pharmacokinetics |
| Swedish | Farmakokinetik |
| Czech | farmakokinetika |
| Finnish | Farmakokinetiikka |
| French | Cinétique d'un médicament, Pharmacocinétique |
| Italian | Cinetica del farmaco, Farmacocinetica |
| Russian | KINETIKA LEKARSTV, FARMAKOKINETIKA, КИНЕТИКА ЛЕКАРСТВ, ФАРМАКОКИНЕТИКА |
| Japanese | 薬物速度論, 毒物動態学, 薬動学, 薬物動態, 動力学-薬物, 動態学-薬物, 薬物動力学, 速度論-薬物, 薬物動態学 |
| Croatian | FARMAKOKINETIKA |
| Polish | Farmakokinetyka, Toksykokinetyka, Kinetyka leku |
| Norwegian | Not Translated[Pharmacokinetics] |
| German | Arzneimittelkinetik, Kinetik, Arzneimittel-, Pharmakokinetik |
| Dutch | Farmacokinetiek |
| Portuguese | Cinética de Drogas, Farmacocinética |
| Spanish | Cinética de Drogas, Farmacocinética |
Ontology: drug metabolism (C0683140)
| Definition (NCI) | A series of chemical modifications of a drug compound by enzymatic activity that make the substrate (drug) more water soluble to allow its clearance from the body. Drug metabolism occurs in two phases: Phase I (biotransformation) involves oxidation, hydroxylation reduction, and hydrolysis. Phase II (conjugation) involves synthesis and conjugation. |
| Definition (CSP) | the buildup and breakdown of drugs for utilization by the organism. |
| Definition (GO) | The chemical reactions and pathways involving a drug, a substance used in the diagnosis, treatment or prevention of a disease; as used here antibiotic substances (see antibiotic metabolism) are considered to be drugs, even if not used in medical or veterinary practice. [GOC:cab2] |
| Concepts | Molecular Function (T044) |
| English | drug metabolic process, drug biotransformation, drugs metabolism, biotransformation drugs, drug metabolism, biotransformation drug, metabolism drug, Drug Metabolism |
Ontology: Bioavailable (C0935763)
| Definition (NCI_NCI-GLOSS) | The ability of a drug or other substance to be absorbed and used by the body. Orally bioavailable means that a drug or other substance that is taken by mouth can be absorbed and used by the body. |
| Concepts | Qualitative Concept (T080) |
| SnomedCT | 115470003 |
| English | bioavailable, Bioavailable (qualifier value), Bioavailable |
| Spanish | biodisponible (calificador), biodisponible |
Ontology: Renal Elimination (C1373187)
| Definition (MSH) | The discharge of substances from the blood supply via the URINARY TRACT. |
| Concepts | Organ or Tissue Function (T042) |
| MSH | D065667 |
| English | Renal Excretion [PK], Elimination, Renal, Renal Excretion, Renal Elimination, Excretion, Renal |
Ontology: Hepatobiliary Elimination (C3850064)
| Definition (MSH) | The removal of substances from the blood supply via the LIVER and BILIARY TRACT. |
| Concepts | Organ or Tissue Function (T042) |
| MSH | D065669 |
| English | Hepatobiliary Elimination, Hepatobiliary Excretion, Excretion, Hepatobiliary, Elimination, Hepatobiliary |
