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Glossary Notation
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
A
coefficient in the equation for plasma drug concentration over time for a two-compartment intravenous bolus model AUC area under the plasma drug concentration versus time curve (AUC) ¥ the area under the plasma concentra0 tion time versus curve from t ¼ 0 to time t ¼ ¥ ARE amount of drug remaining to be eliminated at time t AUMC (area under the [first] moment curve) a synonym for the first statistical R¥ moment: 0 tf ðtÞdt: It is estimated by the trapezoidal approximation of the area under the curve having the product of plasma drug concentration multiplied by time on the ordinate and time on the abscissa. The ratio AUC/AUMC is equal to MRT. B coefficient in the equation for plasma drug concentration over time for a two-compartment intravenous bolus model; it is the y-axis intercept of the terminal log linear segment of the plasma drug concentration versus time curve Cl or Cls systemic clearance of a drug ClH hepatic clearance of a drug Clint intrinsic clearance of a drug 0
Cl int intrinsic free (unbound) clearance of a drug ClNR non-renal clearance of a drug ClR renal clearance of a drug Cp plasma drug concentration at time t following drug administration (Cp)0 plasma drug concentration at t ¼ 0 (immediately) following drug administration) (Cp)max peak plasma concentration after a single oral dose of drug
(Cp)¥ [also (Cp)ss] concentration of drug in the plasma at steady state (Cp ) ss average steady-state plasma drug concentration (Cp¥)max [also (Cpss)max] peak steady-state plasma drug concentration (Cp¥)min [also (Cpss)min] minimum or trough, steady-state plasma drug concentration (Cpn)t plasma drug concentration at a time t after the administration of the nth dose of a multiple dosing regimen (Cp)t0 plasma drug concentration at a time t0 after the cessation of an intravenous infusion (Cp)HI for multiple intravenous infusion, a ‘‘peak’’ concentration that is collected late and that requires mathematical adjustment to estimate the ‘‘peak’’ concentration that would have been recorded if the blood sample had been collected on time (Cp)LO for multiple intravenous infusion, a trough concentration that is collected early and that requires mathematical adjustment to estimate the trough concentration that would have been recorded if the blood sample had been collected on time (Cp)‘‘PK’’ the useable peak concentration for a two-compartment drug administered by multiple intravenous infusion; this occurs when a semilogarithmic plot of plasma drug concentration versus time becomes linear (for vancomycin: approximately 1–2 h after the infusion is stopped) dX/dt instantaneous rate of change in the mass of drug present in the body (exclusive of the gastrointestinal tract) at time t (if dX/dt is positive, mass is increasing over time; if it is negative, mass is decreasing over time) dXe/dt the rate of drug elimination; the rate of loss of drug from the body as a whole; it is
377 EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
378
G lo s sa r y
equal to (þ)KX for one-compartment drugs (both intravenous bolus and oral) and is equal to (þ)k10XC for two-compartment drugs (both intravenous bolus and oral); moreover, it is equal to (dX/dt) for intravenous bolus, but not for oral, dosing dXu/dt the rate of change of drug eliminated by the body by urinary excretion des subscript indicating a desired, or target, plasma drug concentration DL loading dose of drug (DL)inf administered dose of a loading intravenous infusion (DL)IV loading dose administered as an intravenous bolus injection E the hepatic extraction ratiofora drug;itisthe fraction drug metabolized (and eliminated) by the liver during a single pass through the liver f fraction of an oral dose absorbed from the gastrointestinal tract into the portal (not the systemic) circulation; affected predominately by dissolution of drug in the gastrointestinal tract f [in context] fraction drug remaining in the body at time t after an intravenous bolus dose of drug F the fraction of an extravascularly administered dose of drug that is absorbed into the systemic circulation; it is the extent of a drug’s bioavailability fC fraction of total drug in the body that is present in the central compartment at time t fC* fraction of total drug in the body that is present in the central compartment in the post-distribution phase FG extent of systemic absorption for a generic formulation of drug FIV fraction of an intravenous dose reaching the general circulation; by definition, this equals 1.0 FPO [or Foral] fraction of an oral dose reaching the general circulation; it is the product: f F* FS extent of systemic absorption for a standard (trade name) formulation of drug fss for multiple dosing, the ratio of plasma drug concentration at time t to plasma drug concentration that would be achieved at steady-state; fraction of steady state achieved at time t
fup fraction drug unbound in the plasma fut fraction drug unbound in the tissue F* fraction of drug in the portal circulation that goes on to survive the first-pass effect and enter the systemic circulation; it equals 1 E, where E is the hepatic extraction ratio for the drug I coefficient in the equation for plasma drug concentration over time for a one-compartment extravascular model; it is the intercept on the y-axis of the extrapolated terminal linear segment of a semilogarithmic plot of plasma drug concentration (Cp) versus time after an oral dose of drug K (or Kel) the first-order elimination rate constant for a one-compartment drug Ka the first-order absorption rate constant Ke the first-order rate constant for renal excretion of drug Km the first-order rate constant for metabolism of drug; or [in context] the Michaelis constant in non-linear pharmacokinetics K0 the zero-order elimination rate constant Kother the first-order rate constant for elimination of drug by a process other than metabolism or renal excretion K10 for a two-compartment drug, the firstorder rate constant for elimination of drug from the central compartment K12 for a two-compartment drug, the firstorder rate constant for transfer from the central to the peripheral compartment K21 for a two-compartment drug, the firstorder rate constant for transfer from the peripheral to the central compartment MAT mean absorption time; mean residence time in the gastrointestinal tract; synonymous with MRTGIT MDT mean dissolution time in vivo of a solid oral dosage form administered to a human subject MRT mean residence time; the mean (average) time for a mass of intact drug molecules to transit through the body; it is a composite of all disposition processes and, when applicable, drug release from the dosage form and absorption n the dose number (e.g. the fifth dose for n ¼ 5) NaPH abbreviation used for sodium phenytoin
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Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Glossary PH abbreviation used for phenytoin (free acid) Q intravenous infusion rate rate (mass/time units) QH hepatic plasma flow QL the infusion rate of a loading intravenous infusion r the Dost ratio R accumulation factor; [in context] the rate of administration of drug S the salt form correction factor t time; [in context] time since the latest dose in a series of multiple doses was administered t0 time following the cessation of an infusion T time at which the infusion is stopped tinf the duration of an intravenous infusion (time during which the intravenous infusion is being infused into the patient) t0 lagtime (time elapsed after oral dosing until Cp begins to rise above zero tp time of peak plasma drug concentration after a single oral dose 0 t p time of peak plasma drug concentration after multiple oral doses to steady state t1/2 first-order elimination half life V apparent volume of distribution Vb (Vdb) for a two-compartment model drug, the apparent total volume of distribution in the post-distribution phase after a single dose of drug VC apparent volume of distribution of the central compartment for a two-compartment drug Vcirc actual circulatory volume Vmax maximal velocity (rate) of elimination in non-linear (Michaelis–Menten) kinetics Vss (Vdss) for a two-compartment model drug, the apparent total volume of distribution at steady state VTBW volume of total body water X the mass, or amount, of drug present in the body at time t; this does not include any drug that may be present in the gastrointestinal tract Xa the mass, or amount, of drug capable of being absorbed present in the absorption site (e.g. the gastrointestinal tract) at time t (Xa)t¼0 the mass, or amount, of absorbable drug present in the absorption site (e.g. the
379
gastrointestinal tract) at time t ¼ 0; this is equal to FX0 Xbag for statistical moment analysis, the mass of drug remaining in the intravenous infusion bag at time t XC for a two-compartment model drug, the mass of drug present in the central compartment at time t (XC)0 for a two-compartment model drug, the mass of drug present in the central compartment at time t ¼ 0 XGIT mass of drug in the gastrointestinal tract at time t (XGIT)0 mass of drug in the gastrointestinal tract at t ¼ 0 X0 the dose of drug administered (Xinf)0 administered dose of a multiple intermittent intravenous infusion (Xm)t mass of metabolite present in the blood at time t (Xmu)t mass of metabolite present in the urine at time t Xperi for a two-compartment drug, the mass of drug present in the peripheral compartment at time t Xt¼0 mass of drug present in the body at t ¼ 0 (immediately) following drug administration) (Xu)cum cumulative mass of drug excreted in the urine at time t ( X u )¥cum cumulative mass of drug excreted in the urine at time ¼ ¥ X* for a two-compartment model drug, the mass of drug present in the body in the post-distribution phase a the fast disposition rate constant for a twocompartment drug (usually representing the rate of drug distribution) b the slow disposition rate constant for a twocompartment drug; it is derived from the slope of the terminal linear segment of Cp versus time and, in this phase, is usually indicative of elimination of drug from the body as a whole l general term for a rate constant, e.g. K, Ka, b, etc. t fixed dosing interval for a multiple intermittent dose regimen F fluctuation factor at steady state
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
380
G lo s sa r y
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Definitions active transport a type of specialized transport where energy is used to move a drug molecule against a concentration gradient ADME acronym for the pharmacokinetic processes absorption, distribution, metabolism, and excretion absorption the process by which an extravascularly administered drug gets into the systemic circulation adsorption binding on to a surface AUC (area under the [plasma drug concentration versus time] curve) an indicator of extent of absorption of an orally administered drug formulation binding, plasma protein drug binding to albumin and other proteins in the blood; since bound drug is inactive, displacement of drugs from binding sites by other drugs may be important, especially for drugs with a high degree (>90%) of binding bioavailability, extent the fraction (F) of orally administered drug that reaches (is absorbed into) the systemic circulation; it is also called absolute bioavailability bioavailability, rate the rate of absorption of an orally administered drug bioavailability, relative the extent of orally administered drug reaching the systemic circulation compared with that of another extravascular formulation bioequivalence study a study that compares the relative rate and extent of bioavailability (systemic absorption) of a generic drug with the rate and extent of bioavailability of the standard formulation of the same drug; it is the basis of approval of a generic formulation by the US Food and Drug Administration (FDA) bioequivalent a formulation deemed by the FDA to have essentially the same rate and extent of absorption as the standard (see also therapeutic equivalent) circulation, portal blood vessels draining the gastrointestinal tract; orally administered drug traversing the gastrointestinal tract membrane goes into the portal circulation, which conveys it to the liver, where it
may then undergo elimination via the firstpass effect circulation, systemic blood vessels that distribute absorbed drug throughout the body; intravenously administered drug goes directly into the systemic circulation clearance a pharmacokinetic parameter that indicates the volume of plasma from which all drug is removed (cleared) per unit time compartment a virtual space into which absorbed drug can be considered to be distributed; some drugs remain in a central compartment comprising the vasculature and the well-perfused organs and tissues, while other drugs undergo a further transfer into a more peripheral space termed the tissue compartment conjugate acid the substance produced when a weak base gains a proton deaggregation a process by which granules from the disintegration of tablets or capsules are further decreased in size to fine particles diffusion movement of drug molecules that is powered by a concentration gradient; (see passive diffusion and facilitated diffusion] disintegration a process by which a tablet or capsule is broken down into particles called granules dissociation in solution, the physical separation of anions and cations of an acid, a base or a salt; dissociation approaches 100% for most salts and for strong acids and bases, while the degree of dissociation of weak acids and bases is governed by their dissociation constants dissolution the process by which a drug goes into solution in which individual drug molecules are separated by molecules of solvent (water) distribution the process in which a drug molecule is carried by the circulation to well-perfused organs and tissues and, depending on the drug, even more extensively to distant tissues effect response of the body to a pharmacological agent; this response may be either therapeutic or toxic; it is characterized by an onset, intensity, and duration
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Glossary elimination removal of active drug from the body by metabolism and/or excretion processes elimination half life for a drug with linear elimination pharmacokinetics, the time it takes for 50% of drug present to be eliminated; it is constant for a given patient receiving a particular drug elimination pharmacokinetics, linear elimination following a first-order process; in this situation, AUC is a linear function of dose elimination pharmacokinetics, nonlinear elimination following a process other than a first-order process; in this situation, AUC is not a linear function of dose; large changes in steady-state plasma drug concentrations can occur for relatively small changes in dose excretion physical removal of a drug molecule or a metabolite from the body; excretion is predominantly by the kidney (renal excretion) and in the bile (biliary excretion) excipient ingredients in a pharmaceutical formulation, other than the active ingredient, which confer useful properties to the formulation (e.g. disintegrants, lubricants, stabilizing agents) extraction ratio the fraction of drug eliminated from the body during a single pass through an organ of elimination (e.g. the liver) facilitated diffusion diffusion of a drug molecule across a membrane aided by a carrier molecule Fick’s first law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process; linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug generic a formulation of drug prepared by a company that did not innovate the drug; the
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company will present bioequivalency data to the FDA for its approval, with a view to marketing the generic formulation when the innovator drug formulation comes off patent hydrophilic ‘‘water-loving,’’ possessing a low octanol/water partition coefficient ionization charge separation in a molecules, producing electron-depleted cations and electron-rich anions; salts can be fully ionized in the dry state kinetics rate lipid bilayer biological membrane lipophilic ‘‘fat-loving;’’ possessing a high octanol/water partition coefficient metabolism effective removal of a parent drug molecule by converting it to a chemically different species; usually this results in an inactive molecule that is more readily excreted than the parent; phase I and phase II metabolism pathways exist micronization reduction of a drug’s particle size to the mm range; necessary for rapid dissolution of some drugs minimum effective concentration (MEC) the plasma drug concentration below which, on the average, no therapeutic effect occurs minimum toxic concentration (MTC) the plasma drug concentration above which, on the average, toxicity occurs nephron the functional unit of the kidney, comprising glomerulus, tubules and surrounding vasculature Noyes–Whitney equation equation that governs the rate of dissolution of particles of drug octanol/water partition coefficient the amount of drug that goes into the octanol phase compared with the amount of drug that goes into the aqueous phase in a two-phase system; having a larger value for more lipophilic drugs parameter a pharmacokinetic constant for a given patient receiving a particular drug parenteral by injection passive diffusion movement of drug molecules that is powered by a concentration gradient; diffusion occurs across the lipid bilayer (membrane) for lipophilic drugs and via aqueous channels (pores) for small hydrophilic drugs
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
A
coefficient in the equation for plasma drug concentration over time for a two-compartment intravenous bolus model AUC area under the plasma drug concentration versus time curve (AUC) ¥ the area under the plasma concentra0 tion time versus curve from t ¼ 0 to time t ¼ ¥ ARE amount of drug remaining to be eliminated at time t AUMC (area under the [first] moment curve) a synonym for the first statistical R¥ moment: 0 tf ðtÞdt: It is estimated by the trapezoidal approximation of the area under the curve having the product of plasma drug concentration multiplied by time on the ordinate and time on the abscissa. The ratio AUC/AUMC is equal to MRT. B coefficient in the equation for plasma drug concentration over time for a two-compartment intravenous bolus model; it is the y-axis intercept of the terminal log linear segment of the plasma drug concentration versus time curve Cl or Cls systemic clearance of a drug ClH hepatic clearance of a drug Clint intrinsic clearance of a drug 0
Cl int intrinsic free (unbound) clearance of a drug ClNR non-renal clearance of a drug ClR renal clearance of a drug Cp plasma drug concentration at time t following drug administration (Cp)0 plasma drug concentration at t ¼ 0 (immediately) following drug administration) (Cp)max peak plasma concentration after a single oral dose of drug
(Cp)¥ [also (Cp)ss] concentration of drug in the plasma at steady state (Cp ) ss average steady-state plasma drug concentration (Cp¥)max [also (Cpss)max] peak steady-state plasma drug concentration (Cp¥)min [also (Cpss)min] minimum or trough, steady-state plasma drug concentration (Cpn)t plasma drug concentration at a time t after the administration of the nth dose of a multiple dosing regimen (Cp)t0 plasma drug concentration at a time t0 after the cessation of an intravenous infusion (Cp)HI for multiple intravenous infusion, a ‘‘peak’’ concentration that is collected late and that requires mathematical adjustment to estimate the ‘‘peak’’ concentration that would have been recorded if the blood sample had been collected on time (Cp)LO for multiple intravenous infusion, a trough concentration that is collected early and that requires mathematical adjustment to estimate the trough concentration that would have been recorded if the blood sample had been collected on time (Cp)‘‘PK’’ the useable peak concentration for a two-compartment drug administered by multiple intravenous infusion; this occurs when a semilogarithmic plot of plasma drug concentration versus time becomes linear (for vancomycin: approximately 1–2 h after the infusion is stopped) dX/dt instantaneous rate of change in the mass of drug present in the body (exclusive of the gastrointestinal tract) at time t (if dX/dt is positive, mass is increasing over time; if it is negative, mass is decreasing over time) dXe/dt the rate of drug elimination; the rate of loss of drug from the body as a whole; it is
377 EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
378
G lo s sa r y
equal to (þ)KX for one-compartment drugs (both intravenous bolus and oral) and is equal to (þ)k10XC for two-compartment drugs (both intravenous bolus and oral); moreover, it is equal to (dX/dt) for intravenous bolus, but not for oral, dosing dXu/dt the rate of change of drug eliminated by the body by urinary excretion des subscript indicating a desired, or target, plasma drug concentration DL loading dose of drug (DL)inf administered dose of a loading intravenous infusion (DL)IV loading dose administered as an intravenous bolus injection E the hepatic extraction ratiofora drug;itisthe fraction drug metabolized (and eliminated) by the liver during a single pass through the liver f fraction of an oral dose absorbed from the gastrointestinal tract into the portal (not the systemic) circulation; affected predominately by dissolution of drug in the gastrointestinal tract f [in context] fraction drug remaining in the body at time t after an intravenous bolus dose of drug F the fraction of an extravascularly administered dose of drug that is absorbed into the systemic circulation; it is the extent of a drug’s bioavailability fC fraction of total drug in the body that is present in the central compartment at time t fC* fraction of total drug in the body that is present in the central compartment in the post-distribution phase FG extent of systemic absorption for a generic formulation of drug FIV fraction of an intravenous dose reaching the general circulation; by definition, this equals 1.0 FPO [or Foral] fraction of an oral dose reaching the general circulation; it is the product: f F* FS extent of systemic absorption for a standard (trade name) formulation of drug fss for multiple dosing, the ratio of plasma drug concentration at time t to plasma drug concentration that would be achieved at steady-state; fraction of steady state achieved at time t
fup fraction drug unbound in the plasma fut fraction drug unbound in the tissue F* fraction of drug in the portal circulation that goes on to survive the first-pass effect and enter the systemic circulation; it equals 1 E, where E is the hepatic extraction ratio for the drug I coefficient in the equation for plasma drug concentration over time for a one-compartment extravascular model; it is the intercept on the y-axis of the extrapolated terminal linear segment of a semilogarithmic plot of plasma drug concentration (Cp) versus time after an oral dose of drug K (or Kel) the first-order elimination rate constant for a one-compartment drug Ka the first-order absorption rate constant Ke the first-order rate constant for renal excretion of drug Km the first-order rate constant for metabolism of drug; or [in context] the Michaelis constant in non-linear pharmacokinetics K0 the zero-order elimination rate constant Kother the first-order rate constant for elimination of drug by a process other than metabolism or renal excretion K10 for a two-compartment drug, the firstorder rate constant for elimination of drug from the central compartment K12 for a two-compartment drug, the firstorder rate constant for transfer from the central to the peripheral compartment K21 for a two-compartment drug, the firstorder rate constant for transfer from the peripheral to the central compartment MAT mean absorption time; mean residence time in the gastrointestinal tract; synonymous with MRTGIT MDT mean dissolution time in vivo of a solid oral dosage form administered to a human subject MRT mean residence time; the mean (average) time for a mass of intact drug molecules to transit through the body; it is a composite of all disposition processes and, when applicable, drug release from the dosage form and absorption n the dose number (e.g. the fifth dose for n ¼ 5) NaPH abbreviation used for sodium phenytoin
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Glossary PH abbreviation used for phenytoin (free acid) Q intravenous infusion rate rate (mass/time units) QH hepatic plasma flow QL the infusion rate of a loading intravenous infusion r the Dost ratio R accumulation factor; [in context] the rate of administration of drug S the salt form correction factor t time; [in context] time since the latest dose in a series of multiple doses was administered t0 time following the cessation of an infusion T time at which the infusion is stopped tinf the duration of an intravenous infusion (time during which the intravenous infusion is being infused into the patient) t0 lagtime (time elapsed after oral dosing until Cp begins to rise above zero tp time of peak plasma drug concentration after a single oral dose 0 t p time of peak plasma drug concentration after multiple oral doses to steady state t1/2 first-order elimination half life V apparent volume of distribution Vb (Vdb) for a two-compartment model drug, the apparent total volume of distribution in the post-distribution phase after a single dose of drug VC apparent volume of distribution of the central compartment for a two-compartment drug Vcirc actual circulatory volume Vmax maximal velocity (rate) of elimination in non-linear (Michaelis–Menten) kinetics Vss (Vdss) for a two-compartment model drug, the apparent total volume of distribution at steady state VTBW volume of total body water X the mass, or amount, of drug present in the body at time t; this does not include any drug that may be present in the gastrointestinal tract Xa the mass, or amount, of drug capable of being absorbed present in the absorption site (e.g. the gastrointestinal tract) at time t (Xa)t¼0 the mass, or amount, of absorbable drug present in the absorption site (e.g. the
379
gastrointestinal tract) at time t ¼ 0; this is equal to FX0 Xbag for statistical moment analysis, the mass of drug remaining in the intravenous infusion bag at time t XC for a two-compartment model drug, the mass of drug present in the central compartment at time t (XC)0 for a two-compartment model drug, the mass of drug present in the central compartment at time t ¼ 0 XGIT mass of drug in the gastrointestinal tract at time t (XGIT)0 mass of drug in the gastrointestinal tract at t ¼ 0 X0 the dose of drug administered (Xinf)0 administered dose of a multiple intermittent intravenous infusion (Xm)t mass of metabolite present in the blood at time t (Xmu)t mass of metabolite present in the urine at time t Xperi for a two-compartment drug, the mass of drug present in the peripheral compartment at time t Xt¼0 mass of drug present in the body at t ¼ 0 (immediately) following drug administration) (Xu)cum cumulative mass of drug excreted in the urine at time t ( X u )¥cum cumulative mass of drug excreted in the urine at time ¼ ¥ X* for a two-compartment model drug, the mass of drug present in the body in the post-distribution phase a the fast disposition rate constant for a twocompartment drug (usually representing the rate of drug distribution) b the slow disposition rate constant for a twocompartment drug; it is derived from the slope of the terminal linear segment of Cp versus time and, in this phase, is usually indicative of elimination of drug from the body as a whole l general term for a rate constant, e.g. K, Ka, b, etc. t fixed dosing interval for a multiple intermittent dose regimen F fluctuation factor at steady state
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
380
G lo s sa r y
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Definitions active transport a type of specialized transport where energy is used to move a drug molecule against a concentration gradient ADME acronym for the pharmacokinetic processes absorption, distribution, metabolism, and excretion absorption the process by which an extravascularly administered drug gets into the systemic circulation adsorption binding on to a surface AUC (area under the [plasma drug concentration versus time] curve) an indicator of extent of absorption of an orally administered drug formulation binding, plasma protein drug binding to albumin and other proteins in the blood; since bound drug is inactive, displacement of drugs from binding sites by other drugs may be important, especially for drugs with a high degree (>90%) of binding bioavailability, extent the fraction (F) of orally administered drug that reaches (is absorbed into) the systemic circulation; it is also called absolute bioavailability bioavailability, rate the rate of absorption of an orally administered drug bioavailability, relative the extent of orally administered drug reaching the systemic circulation compared with that of another extravascular formulation bioequivalence study a study that compares the relative rate and extent of bioavailability (systemic absorption) of a generic drug with the rate and extent of bioavailability of the standard formulation of the same drug; it is the basis of approval of a generic formulation by the US Food and Drug Administration (FDA) bioequivalent a formulation deemed by the FDA to have essentially the same rate and extent of absorption as the standard (see also therapeutic equivalent) circulation, portal blood vessels draining the gastrointestinal tract; orally administered drug traversing the gastrointestinal tract membrane goes into the portal circulation, which conveys it to the liver, where it
may then undergo elimination via the firstpass effect circulation, systemic blood vessels that distribute absorbed drug throughout the body; intravenously administered drug goes directly into the systemic circulation clearance a pharmacokinetic parameter that indicates the volume of plasma from which all drug is removed (cleared) per unit time compartment a virtual space into which absorbed drug can be considered to be distributed; some drugs remain in a central compartment comprising the vasculature and the well-perfused organs and tissues, while other drugs undergo a further transfer into a more peripheral space termed the tissue compartment conjugate acid the substance produced when a weak base gains a proton deaggregation a process by which granules from the disintegration of tablets or capsules are further decreased in size to fine particles diffusion movement of drug molecules that is powered by a concentration gradient; (see passive diffusion and facilitated diffusion] disintegration a process by which a tablet or capsule is broken down into particles called granules dissociation in solution, the physical separation of anions and cations of an acid, a base or a salt; dissociation approaches 100% for most salts and for strong acids and bases, while the degree of dissociation of weak acids and bases is governed by their dissociation constants dissolution the process by which a drug goes into solution in which individual drug molecules are separated by molecules of solvent (water) distribution the process in which a drug molecule is carried by the circulation to well-perfused organs and tissues and, depending on the drug, even more extensively to distant tissues effect response of the body to a pharmacological agent; this response may be either therapeutic or toxic; it is characterized by an onset, intensity, and duration
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
Copyright © 2009. Royal Pharmaceutical Society of Great Britain All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.
Glossary elimination removal of active drug from the body by metabolism and/or excretion processes elimination half life for a drug with linear elimination pharmacokinetics, the time it takes for 50% of drug present to be eliminated; it is constant for a given patient receiving a particular drug elimination pharmacokinetics, linear elimination following a first-order process; in this situation, AUC is a linear function of dose elimination pharmacokinetics, nonlinear elimination following a process other than a first-order process; in this situation, AUC is not a linear function of dose; large changes in steady-state plasma drug concentrations can occur for relatively small changes in dose excretion physical removal of a drug molecule or a metabolite from the body; excretion is predominantly by the kidney (renal excretion) and in the bile (biliary excretion) excipient ingredients in a pharmaceutical formulation, other than the active ingredient, which confer useful properties to the formulation (e.g. disintegrants, lubricants, stabilizing agents) extraction ratio the fraction of drug eliminated from the body during a single pass through an organ of elimination (e.g. the liver) facilitated diffusion diffusion of a drug molecule across a membrane aided by a carrier molecule Fick’s first law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process; linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug generic a formulation of drug prepared by a company that did not innovate the drug; the
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company will present bioequivalency data to the FDA for its approval, with a view to marketing the generic formulation when the innovator drug formulation comes off patent hydrophilic ‘‘water-loving,’’ possessing a low octanol/water partition coefficient ionization charge separation in a molecules, producing electron-depleted cations and electron-rich anions; salts can be fully ionized in the dry state kinetics rate lipid bilayer biological membrane lipophilic ‘‘fat-loving;’’ possessing a high octanol/water partition coefficient metabolism effective removal of a parent drug molecule by converting it to a chemically different species; usually this results in an inactive molecule that is more readily excreted than the parent; phase I and phase II metabolism pathways exist micronization reduction of a drug’s particle size to the mm range; necessary for rapid dissolution of some drugs minimum effective concentration (MEC) the plasma drug concentration below which, on the average, no therapeutic effect occurs minimum toxic concentration (MTC) the plasma drug concentration above which, on the average, toxicity occurs nephron the functional unit of the kidney, comprising glomerulus, tubules and surrounding vasculature Noyes–Whitney equation equation that governs the rate of dissolution of particles of drug octanol/water partition coefficient the amount of drug that goes into the octanol phase compared with the amount of drug that goes into the aqueous phase in a two-phase system; having a larger value for more lipophilic drugs parameter a pharmacokinetic constant for a given patient receiving a particular drug parenteral by injection passive diffusion movement of drug molecules that is powered by a concentration gradient; diffusion occurs across the lipid bilayer (membrane) for lipophilic drugs and via aqueous channels (pores) for small hydrophilic drugs
EBSCO Publishing - NetLibrary; printed on 10/27/2010 7:11:05 AM via s2054655-EbooksBiomedicalTrial-001 eISBN:9780853697725; Jambhekar, Sunil.; Breen, Philip J. : Basic Pharmacokinetics Account: 26637700
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