Drug Distribution

Drug Distribution Dr. Robert G. Lamb Professor Pharmacology & Toxicology

Distribution & Volume of Distribution Distribution: the passage of drugs from blood to tissues. Volume of Distribution (Vd): apparent volume of body water that drug appears to distribute into to produce a drug concentration equal to that in the blood.

Key factor in the onset of drug action.

Distribution of Drugs PLASMA

Extracellular Fluid

Intracellular

Drug Bound to Nonactive Sites

Drug Bound to Nonactive Sites

Body Water Compartments BODY WATER COMPARTMENTS:

50Kg (110 lb)

Total body water (60% body weight) = 0.6 L/Kg, 30 L

Drug

Free Drug

Free Drug

DISTRIBUTION Capillary Endothelium

Drug Bound to Receptor Cellular (Biologic Effect)

Extracellular

(20% body weight) = 0.2L/Kg,

& 100Kg (220 lb)

&

60 L

10 L &

20 L

Plasma

(4% body weight) = 0.04L/Kg,

2 L &

4L

Interstitial

(16% body weight) = 0.16L/Kg,

8 L &

16 L

Intracellular

(40% body weight) = 0.4 L/Kg, 20 L &

40 L

Membrane

Volume of Distribution (L) Expressed as liters of body water in a 70 (154 lb) Kg man. Vd = Q/C Q = amount of drug in body (g) C = unbound plasma drug concentration (g/liter) Calculate Vd when 1 g is administered iv and the plasma drug level is 0.024 g/L.

Volume of Distribution (% BW) Expressed as % of body weight in a 70 Kg man. Vd = (Q)(100)/(C) (body weight in Kg) Q = drug dose C = plasma drug level Vd = (1 g)(100)/(.024 g/L)(70) = 60% (Total Body Water)

Vd = 1 g/.024 g/L = 42 L (Total Body Water)

1

Plasma Protein Binding D + P ↔ DP Zn ++ , lipids Cholesterol Vitamins A, K, D, E

Cu++ (Ceruloplasmin) Lithium carmine Hemoglobin (Haptoglobin)

γ

β2

β1

Fe ++ (Transferrin)

α2

α1

Albumin

Ca ++ , Cu ++ , Zn ++ Bilirubin Uric acid Vitamin C Adenosine Tetracyclines Chloramphenicol Digitonin Fatty acids Suramin Quinacrine Penicllin Salicylate Para-aminosalicylate Sulfonamides Steptomycin Acid dyes Phenol red Histamine Triiodothyronine Thyroxine Barbiturates

Plasma Protein Binding of Drugs D + P ↔ DP (reversible binding) Bound drug is in equilibrium with free drug. Free drug is active and bound drug is inactive. More free drug when binding sites are saturated. Competition between drugs for binding sites.

Steroid hormones (Transcortin) Vitamin B 12 Sialic acid Thyroxine

Percent of Protein Bound Drug [I]

Percent of Protein Bound Drug [II]

Drug is 90% bound to plasma protein. What % of total drug is bound if drug’s Vd is: Patient is a 30 year old male weighing 70 Kg. What % of total drug is bound if drug’s Vd is: Vd = 3 L (PLASMA) 90% PD × 3 L = 270 PD; 10% D × 3 L = 30 D Total Drug = PD + D = 300; % PD = 270/300 = 90%

Vd = 14 L (EXTRACELLULAR BODY WATER) 90% PD × 3 L = 270 PD; 10% D × 14 L = 140 D Total Drug = PD + D = 410; % PD = 270/410 = 66% % of total drug bound (66%) is less than blood PD %.

% of total drug bound (90%) is equal to plasma PD %.

Percent of Protein Bound Drug [III]

Passage of Drugs Across Membranes Barrier

What % of total drug is bound if drug’s Vd is:

Fluid compartments Plasma

Vd = 42 L (TOTAL BODY WATER) [70 Kg] 90% PD × 3 L = 270 PD; 10% D × 42 L = 420 D Total Drug = PD + D = 690; % PD = 270/690 = 39.1%

Drug characteristics

Fick’s Law % total drug bound (39.1) is less than plasma PD % . As Vd increases the % of total drug bound decreases.

Capillary membrane

Cell membrane

Interstitial fluid

Intracellular fluid Mechanism responsible for passage

Small molecule

Filtration

Lipid-soluble

Diffusion

Carrier

Lipid-insoluble Large molecule

Key Factor

Protein-bound

No active transport Active transport

2

Phenobarbital[PB] Poisoning ECF

PB weak acid

pH

More PB

pKa = 7.2 CNS Depressant

Less PB

Brain

7.4

7.0

7.0

7.0

6.5

7.0

Less PB

More PB More PB

Less PB Membrane Give I.V. NaHCO3

Blood Flow to Various Tissues Rapidly perfused (ml/100 g/min) tissues respond quickly Brain (55) Liver (20) Kidney (450) Less rapidly perfused tissues respond to drug more slowly Muscle (3) Skin (5) Poorly perfused tissues respond very slowly to drug Fat (1)

↑ ECF pH; ↓ Brain PB

Drug Distribution in CNS Aging Effect on Drug Distribution

Arterial Blood

Increased fat and decreased lean body mass (higher Vd of some drugs) Decreased total and % body water ( lower Vd of some drugs) Decrease in serum albumin (more free drug)

Intracellular Fluid Compartment of Brain Cells

Blood-Brain Barrier

Blood-CSF Barrie

(capillary endothelium, astrocytic sheath)

(capillary endothelium, epithelium of choroid plexus)

Extracellular Fluid Compartment of Brain

Brain - CSF Barrier

Cerebrospinal Fluid Compartment

(ventricles and space of CNS)

Venous Blood

Fetal Drug Distribution Most drugs readily distribute by passive diffusion Epithelium of villi is the only major barrier Endothelium of capillaries

Risks Abortion and abnormal development [Cocaine, Tamoxifen] Malformation [Thalidomide, Methotrexate, Organic Solvents] Alter behavior and intelligence [Alcohol, Cocaine, Amphetamines] Produce cancer later in life [Diethylstibesterol] Dependence/Withdrawal [Heroin, Morphine and Cocaine] Intrauterine growth retardation, prematurity, SIDS [Smoking]

Drug Reservoirs Stomach ionizes basic drugs and traps them (pH effect) Albumin binds various drugs and limits distribution Tissues such as the liver can avidly bind drugs (chloroquine) Lipid soluble compounds can localize in fat tissue (thiopental)

3

Redistribution of Thiopental % of Dose

100

Plasma

Lean Brain

50

0

1

Fat

15

30

60

Time (minutes)

4