compartmental analysis of drug distribution l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION PowerPoint Presentation
Download Presentation
COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION

Loading in 2 Seconds...

play fullscreen
1 / 81

COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION - PowerPoint PPT Presentation


  • 492 Views
  • Uploaded on

COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION. Arthur J. Atkinson, Jr., M.D. Senior Advisor in Clinical Pharmacology Clinical Center, NIH. DRUG DISTRIBUTION. THE POST-ABSORPTIVE TRANSFER OF DRUG FROM ONE LOCATION IN THE BODY TO ANOTHER. GOALS OF DRUG DISTRIBUTION LECTURE.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION' - locke


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
compartmental analysis of drug distribution

COMPARTMENTAL ANALYSISOF DRUG DISTRIBUTION

Arthur J. Atkinson, Jr., M.D.

Senior Advisor in Clinical Pharmacology

Clinical Center, NIH

drug distribution
DRUG DISTRIBUTION

THE POST-ABSORPTIVE TRANSFER OF DRUG FROM ONE LOCATION IN THE BODY TO ANOTHER

goals of drug distribution lecture
GOALS OF DRUG DISTRIBUTION LECTURE
  • SIGNIFICANCE OF DRUG DISTRIBUTION
  • VOLUMES
  • PHYSIOLOGIC BASIS OF MULTI-
  • COMPARTMENT PHARMACOKINETIC
  • MODELS
  • CLINICAL IMPLICATIONS OF DRUG
  • DISTRIBUTION KINETICS
drugs with v d corresponding to physiological fluid spaces
DRUGS WITH Vd CORRESPONDING TO PHYSIOLOGICAL FLUID SPACES

INTRAVASCULAR SPACE:

NONE

EXTRACELLULAR FLUID SPACE:

INULIN

PROTEINS & OTHER MACROMOLECULES

NEUROMUSCULAR BLOCKING DRUGS (N+)

AMINOGLYCOSIDE ANTIBIOTICS (initially)

TOTAL BODY WATER:

UREA

CAFFEINE

ETHYL ALCOHOL

ANTIPYRINE (some protein binding)

factors affecting v d estimates of most drugs
FACTORS AFFECTING VdESTIMATESOF MOST DRUGS

BINDING TO PLASMA PROTEINS:

THYROXINE

THEOPHYLLINE

TISSUE BINDING (PARTITIONING):

DIGOXIN (Na+ - K+ ATPase)

LIPOPHILIC COMPOUNDS

physiological spaces for drug distribution
PHYSIOLOGICAL SPACES FOR DRUG DISTRIBUTION

CELL MEMBRANES

ICF

ECF

ELIMINATION

effect of binding changes on v d of thyroxine theophylline
EFFECT OF BINDING CHANGES ON Vd OF THYROXINE & THEOPHYLLINE*

fu is the “free fraction”, the fraction of drug in plasma that is not bound to plasma proteins.

* Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

impact of protein binding on thyroxine distribution volume
IMPACT OF PROTEIN BINDING ON THYROXINE DISTRIBUTION VOLUME*

fu=0.03%

Vd = VECF

* From Larsen PR, Atkinson AJ Jr, et al. J Clin Invest 1970;49:1266-79.

impact of protein binding on theophylline distribution volume
IMPACT OF PROTEIN BINDING ON THEOPHYLLINE DISTRIBUTION VOLUME*

fu=60%

Vd = VECF + fuVICF

* From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

basis for increased theophylline v d in pregnancy
BASIS FOR INCREASED THEOPHYLLINE Vd IN PREGNANCY

* From Frederiksen MC, et al. Clin Pharmacol Ther 1986;40;321-8.

effect of binding changes on v d of most drugs
EFFECT OF BINDING CHANGES ON VdOF MOST DRUGS*

Ф is the ratio of tissue/plasma drug concentration.

* Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

lipid solubility

VD (L/kg) fU Ф

OCTANOL/WATER PARTITION COEF. = 10 – 100*

PHENYTOIN 0.64 0.08 12

DIAZEPAM 1.10 0.013 185

OCTANOL/WATER PARTITION COEF. = 100 - >1000*

PROPRANOLOL 4.30 0.13 82

NORTRIPTYLINE 18.0 0.08 572

*measured at pH 7

LIPID SOLUBILITY & 
apparent v d of digoxin
APPARENT Vd OF DIGOXIN

Φrepresents binding to Na+-K+ ATPase.

goals of drug distribution lecture18
GOALS OF DRUG DISTRIBUTION LECTURE
  • SIGNIFICANCE OF DRUG DISTRIBUTION
  • VOLUMES
  • PHYSIOLOGIC BASIS OF MULTI-
  • COMPARTMENT PHARMACOKINETIC
  • MODELS
  • CLINICAL IMPLICATIONS OF DRUG
  • DISTRIBUTION KINETICS
basic pharmacokinetic models
BASIC PHARMACOKINETIC MODELS*

* From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

mathematical vs physical models
MATHEMATICAL VS. PHYSICAL MODELS*

MATHEMATICAL MODEL:

FUNCTIONS OR DIFFERENTIAL EQUATIONS ARE EMPLOYED WITHOUT REGARD TO ANY MECHANISTIC ASPECTS OF THE SYSTEM

PHYSICAL MODEL:

IMPLIES CERTAIN MECHANISMS OR ENTITIES THAT HAVE PHYSIOLOGICAL, BIOCHEMICAL OR PHYSICAL SIGNIFICANCE

* Berman M: The formulation and testing of models.

Ann NY Acad Sci 1963;108:182-94

first multicompartmental analysis of drug distribution
FIRST MULTICOMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION*

* FromTeorell T. Arch Intern Pharmacodyn 1937;57:205-25.

is central compartment intravascular space
IS CENTRAL COMPARTMENT INTRAVASCULAR SPACE?
  • USUALLY NOT IDENTIFIED AS SUCH
  • UNLESS DRUG GIVEN RAPIDLY IV
  • NEED TO CONSIDER:
  • - IF DISTRIBUTION LIMITED TO ECF,
  • COMPARE VC WITH PLASMA VOLUME.
  • - IF LARGER DISTRIBUTION VOLUME,
  • COMPARE VC WITH BLOOD VOLUME
  • ACCOUNTING FOR RBC/ PLASMA.
if v c is based on plasma concentration measurements
IF VC IS BASED ON PLASMA CONCENTRATION MEASUREMENTS

RBC/P = red cell/plasma partition ratio

Hct = hematocrit

analysis of pa napa central compartment volumes
ANALYSIS OF PA & NAPA CENTRAL COMPARTMENT VOLUMES*

* From Stec GP, Atkinson AJ Jr. J Pharmacokinet Biopharm 1981;9:167-80.

analysis of experimental data
ANALYSIS OF EXPERIMENTAL DATA

HOW MANY COMPARTMENTS?

DESPITE AVAILABILITY OF COMPUTER PROGRAMS FOR PK ANALYSIS, STILL NEED TO MAKE INITIAL ESTIMATES.

compartmental analysis

Dose

k21

Central

V1

Periph.

V2

k01

k12

COMPARTMENTAL ANALYSIS

DATA EQUATION:

C = A´e-αt+ B´e-βt

MODEL EQUATION:

dX1/dt = -(k0 + k12)X1 + k21X2

two compartment model

Dose

Central

V1

Periph.

V2

CLI

CLE

TWO-COMPARTMENT MODEL

Vd(ss) = V1 + V2

two compartment model31

Dose

Central

V1

Periph.

V2

CLI

CLE

k01

TWO-COMPARTMENT MODEL

CLE = k01V1

intercompartmental clearance
INTERCOMPARTMENTAL CLEARANCE*

A VOLUME-INDEPENDENT PARAMETER CHARACTERIZING THE RATE OF ANALYTE TRANSFER BETWEEN COMPARTMENTS OF A KINETIC MODEL

* FromSaperstein et al. Am J Physiol 1955;181:330-6.

two compartment model33

Dose

k21

Central

V1

Periph.

V2

CLI

k12

CLE

TWO-COMPARTMENT MODEL

CLI = k21 V1 = k12 V2

analysis of inulin kinetics with a 2 compartment model

[INULIN] (mg/dL)

AFTER INFUSION

AFTER BOLUS

MINUTES

ANALYSIS OF INULIN KINETICS WITH A 2-COMPARTMENT MODEL*

* Gaudino M. Proc Soc Exper Biol Med 1949;70:672-4.

3 compartment model of inulin kinetics

CELL MEMBRANES

3-COMPARTMENT MODEL OF INULIN KINETICS

EXTRACELLULAR FLUID

VF

Dose

CLF

VC

CLS

VS

CLE

pk pd study of insulin enhancement of skeletal muscle glucose uptake
PK-PD STUDY OF INSULIN ENHANCEMENT OF SKELETAL MUSCLE GLUCOSE UPTAKE*

* From Sherwin RS, et al. J Clin Invest 1974;53:1481-92.

multicompartmental model of inulin and urea kinetics
MULTICOMPARTMENTAL MODEL OF INULIN AND UREA KINETICS*

* From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.

role of transcapillary exchange
ROLE OF TRANSCAPILLARY EXCHANGE

THE CENTRAL COMPARTMENT FOR BOTH UREA AND INULIN IS INTRAVASCULAR SPACE.

THEREFORE, TRANSCAPILLARY EXCHANGE IS THE RATE-LIMITING STEP IN THE DISTRIBUTION OF BOTH COMPOUNDS TO THE PERIPHERAL COMPARTMENTS OF THE MAMMILLARY 3-COMPARTMENT MODEL.

renkin equation
RENKIN EQUATION*

Q = capillary blood flow

P = capillary permeability coefficient-surface

area product (sometimes denoted P•S).

* From Renkin EM.Am J Physiol 1953;183:125-36.

3 compartment model

Dose

VC

CLE

3-COMPARTMENT MODEL

VF

CLF = QF (1 – e PF/QF)

CLS = QS (1 – e PS/QS)

VS

simultaneous analysis of inulin and urea 15 n 2 kinetics

SUBJECT 1

INULIN

UREA

SIMULTANEOUS ANALYSIS OF INULIN AND UREA-15N2 KINETICS

How does QF + QS compare with C.O.?

for each compartment

3 UNKNOWNS:

3 EQUATIONS:

FOR EACH COMPARTMENT

U = urea; I = inulin

D = free water diffusion coefficient

cardiac output and compartmental blood flows
CARDIAC OUTPUT AND COMPARTMENTAL BLOOD FLOWS*

* From Odeh YK, et al. Clin Pharmacol Ther 1993;53;419-25.

mechanisms of transcapillary exchange
MECHANISMS OF TRANSCAPILLARYEXCHANGE

DIFFUSIVE TRANSFER:

M.W. < 6,000 DALTONS

CONVECTIVE TRANSFER:

M.W. > 50,000 DALTONS

capillary permeability vs m w
CAPILLARY PERMEABILITY VS. M.W.*

* From Dedrick RL, Flessner MF. Immunity to Cancer 1989;II:429-38.

mechanisms of transcapillary exchange52
MECHANISMS OF TRANSCAPILLARYEXCHANGE
  • TRANSFER OF SMALL MOLECULES (M.W. < 6,000 Da):
  • TRANSFER PROPORTIONAL TO D
  • - POLAR, UNCHARGED (urea, inulin)
  • TRANSFER RATE < PREDICTED FROM D
  • - HIGHLY CHARGED (quaternary compounds)
  • - INTERACT WITH PORES (procainamide)
  • TRANSFER RATE > PREDICTED FROM D
  • -LIPID SOLUBLE COMPOUNDS (anesthetic gases)

- FACILITATED DIFFUSION (theophylline)

theophylline i c clearance and compartmental blood flows
THEOPHYLLINE I.C. CLEARANCE AND COMPARTMENTAL BLOOD FLOWS*

* From Belknap SM, et al. J Pharmacol Exp Ther 1987;243:963-9.

urea theophylline diffusion coefficients
UREA & THEOPHYLLINE DIFFUSION COEFFICIENTS*

* From Belknap SM, et al. J Pharmacol Exp Ther 1987;243;963-9.

significance of drug distribution rate
SIGNIFICANCE OF DRUG DISTRIBUTION RATE
  • AFFECTS TOXICITY OF IV INJECTED DRUGS
  • THEOPHYLLINE
  • DELAYS ONSET OF DRUG ACTION
  • DIGOXIN
  • INSULIN
  • TERMINATES ACTION AFTER BOLUS DOSE
  • THIOPENTAL
  • LIDOCAINE
early benefits later risks of initial iv theophylline doses
EARLY BENEFITS & LATER RISKS OF INITIAL IV THEOPHYLLINE DOSES

1937 – THEOPHYLLINE 1st USED SUCCESSFULLY

TO TREAT “STATUS ASTHMATICUS”

Herrman G, Aynesworth MB. J Lab Clin Med 1937;23:135-48.

1943 – 3 CASES OF ARRHYTHMIC DEATH AFTER

“SLOW IV INJECTION” OF 200 mg THEOPHYLLINE

Merrill GA. JAMA 1943;123:1115.

1948 – 3 CASES OF CONVULSIVE CARDIORESPIRATORY

DEATH AFTER “SLOW BUT UNMEASURED

INJECTION” OF 88 - 300 mg THEOPHYLLINE

Bresnick E, et al. JAMA 1948;136:397-8.

1971 - IV INJECTION OF 250 – 750 mg THEOPHYLLINE

OVER 3 - 5 min RESULTS IN 60% OF DRUG-RELATED

CARDIAC ARRESTS IN LA COUNTY SHOCK WARD

Camarata, et al. Circulation 1971;44:688-95.

safety linked to rate of theophylline administration
SAFETY LINKED TO RATE OFTHEOPHYLLINE ADMINISTRATION
  • “THE TOTAL DOSE …..DOES NOT SEEM TO BE
  • IMPORTANT, WITHIN THERAPEUTIC LIMITS, THE
  • FATAL DOSE HAVING VARIED FROM 0.1 Gm TO
  • 0.36 Gm. IT IS QUITE POSSIBLE THAT THE SPEED
  • OF INJECTION IS MORE IMPORTANT.”
  • Bresnick E, et al. JAMA 1948;136:397-8.
  • CURRENT RECOMMENDATION:
  • IV THEOPHYLLINE LOADING DOSE SHOULD BE
  • 5 mg/kg INFUSED OVER 20 – 40 min.
pk model of theophylline distribution

SPLANCHNIC

IV Dose

CNS

CLF = QF

IVS

HEART

SOMATIC

CLS = QS

CLE

PK MODEL OF THEOPHYLLINE DISTRIBUTION

CO = QF + QS

significance of drug distribution rate61
SIGNIFICANCE OF DRUG DISTRIBUTION RATE
  • AFFECTS TOXICITY OF IV INJECTED DRUGS
  • THEOPHYLLINE
  • DELAYS ONSET OF DRUG ACTION
  • DIGOXIN
  • INSULIN
  • TERMINATES ACTION AFTER BOLUS DOSE
  • THIOPENTAL
  • LIDOCAINE
significance of drug distribution rate64
SIGNIFICANCE OF DRUG DISTRIBUTION RATE
  • AFFECTS TOXICITY OF IV INJECTED DRUGS
  • THEOPHYLLINE
  • DELAYS ONSET OF DRUG ACTION
  • DIGOXIN
  • INSULIN
  • TERMINATES ACTION AFTER BOLUS DOSE
  • THIOPENTAL
  • LIDOCAINE
distribution terminates effect of bolus lidocaine dose
DISTRIBUTION TERMINATES EFFECT OF BOLUS LIDOCAINE DOSE*

THERAPEUTIC RANGE

* From Atkinson AJ Jr. In: Melmon KL, ed. Drug Therapeutics: Concepts for Physicians, 1981:17-33.

analysis of lidocaine distribution kinetics
ANALYSIS OF LIDOCAINE DISTRIBUTION KINETICS*

* From Benowitz N, et al. Clin Pharmacol Ther 1974;16:87-98.

consequences of very slow drug distribution
CONSEQUENCES OF VERYSLOW DRUG DISTRIBUTION
  • “FLIP-FLOP” KINETICS
  • EFFECTIVE HALF-LIFE
  • PSEUDO DOSE DEPENDENCY
gentamicin elimination phase preceeds its distribution phase
GENTAMICIN ELIMINATION PHASE PRECEEDS ITS DISTRIBUTION PHASE*

* From Schentag JJ, et al. JAMA 1977;238:327-9.

gentamicin elimination in a nephrotoxic vs non toxic patient
GENTAMICIN ELIMINATION IN A NEPHROTOXIC VS. NON-TOXIC PATIENT*

NEPHROTOXIC

NON-TOXIC

* From Coburn WA, et al. J Pharmacokinet Biopharm 1978;6:179-86.

consequences of very slow drug distribution70
CONSEQUENCES OF VERYSLOW DRUG DISTRIBUTION
  • “FLIP-FLOP” KINETICS
  • EFFECTIVE HALF-LIFE
  • PSEUDO DOSE DEPENDENCY
tolrestat cumulation with repeated dosing
TOLRESTAT CUMULATION WITH REPEATED DOSING*

*From Boxenbaum H, Battle M: J Clin Pharmacol 1995;35:763-6.

tolrestat cumulation
TOLRESTAT CUMULATION

OBSERVED C. F. (τ = 12 hr): 1.29

PREDICTED (T½ = 31.6 hr): 4.32

effective half life
EFFECTIVE HALF- LIFE*

* From Boxenbaum H, Battle M. J Clin Pharmacol 1995;35:763-66.

effective half life of tolrestat
EFFECTIVE HALF-LIFE OF TOLRESTAT*

* From Boxenbaum H, Battle M. J Clin Pharmacol 1995;35:763-66.

compartmental analysis of drug distribution78
COMPARTMENTAL ANALYSIS OF DRUG DISTRIBUTION
  • PARAMETERS OF COMPARTMENTAL
  • MODELS
  • THREE DIFFERENT DISTRIBUTION
  • VOLUMES
  • TECHNIQUE OF CURVE PEELING
two compartment model79

Dose

k21

Central

V1

Periph.

V2

CLI

k12

CLE

TWO-COMPARTMENT MODEL

k01