Pharmacokinetics Exam 2 Concepts

What is a multi-compartment model?

-the body does NOT act like a single compartment

-it takes time to distribute into peripheral compartments

Multi compartment distribution (two compartment)

Point 1: end of injection (central into peripheral)

Point 2: distribution in process

Point 3: distribution equilibrium attained

Point 4: elimination process predominates

Two compartment model

method of residuals to calculate slope and intercept for each phase

One compartment model vs. multi-compartment model PK after IV infusion

multi compartment accounts for drug distribution into different tissues, leading to complex concentration-time profiles

Drug Distribution

refers to a reversible transfer of a drug between circulating blood and extra-vascular fluids and tissues of the body

-affected by: properties of drug, anatomy and physiology, disease states, other drugs

Properties of drug

-lipophilicity, size, pKa

-protein binding in plasma and tissues

anatomy and physiology

tissue composition, transporters, other barriers

other drugs

inhibitors of transporters

Drug distribution can be characterized by...

rate and extent

rate of drug distribution depends on...

-perfusion of tissue

-membrane permeability

Extent of drug distribution depends on...

-lipid solubility

-pH-pKa

-plasma protein binding

-tissue protein binding

Cyclosporine A tissue PK

-most tissues show a rapid decline in cyclosporine A concentration = fast distribution and elimination

-skin, fat, thymus exhibit initial increase in concentration before declining, possibly indicating delayed distribution or accumulation

Passive Permeability (passive diffusion)

-bidirectional (reversible)

-dependent on: properties of barrier, properties of drug, concentration gradient

Drug properties affecting membrane permeability

-size (molecular weight)

-lipophilicity

-charge (ionization state)

-being a substrate to a transporter

example of drug transporters and distribution

P-glycoprotein significantly limits distribution of ondansetron into the CNS

Perfusion-rate limitations (delivery rate limitations)

-when tissue membranes present essentially no barrier to distribution (likely for small, lipophilic molecules)

-BLOOD FLOW is a RATE LIMITING step

-well-perfused tissues take up a drug more rapidly than poorly perfused tissues

Perfusion rate in decreasing order

Kidneys (4) > Brain (0.5) > Adipose (0.025)

Permeability-rate limitations (delivery rate limitations)

-crossing the membranes is the rate-limiting step

-common for polar drugs

-physiochemical properties of the drug can significantly influence the permeability (pKa, LogP, LogD)

Vd vs. Physiological Volumes

breaks down total body water into three main compartments

1. plasma

2. interstitial fluid

3. intracellular fluid

-fluid intake and output (via kidneys, lungs, feces, sweat, and skin)

Volume of Distribution (Vd)

describes relationship between amount of drug in the body and the concentration in the blood (plasma)

-proportionally constant

-has no direct physiological meaning

-Vc, Vss, Varea

Apparent Volume of Distribution

-numerical value may be similar to a physiological space in the body

-apparent volume DOES NOT necessarily correspond to a physiological volume

Why are we interested in Vd?

it can be used for calculating the dose

Dose = C x Vd

Protein Binding

- Drug + Protein = Drug Protein Comlex

-fraction unbound

-fraction bound

-most methods measure Ctotal

-total amount of drug in the body is independent of measurement method

acidic drugs commonly bind to ablumin

basic drugs commonly bind to alpha-1 acid glycoprotein

Between Subject variability in fu and Vd (propanolol example)

different health conditions can affect how much of a drug is free in the blood and how widely it spreads in the body

-as alpha 1-acid glycoprotein levels increase, fraction unbound decreases (varies across disease states)

Extent of Distribution

-Vd increases when fu,p is increased

-Vd decreases when Fu,t is increased

-fu,t is the average value across all tissues into which drug distributes

-Kp can vary considerably among tissues

Different values of Vd

Vc (V1) - volume of the central compartment

Vextrap - extrapolated volume

Varea - volume at the terminal phase

Vss - volume at steady-state

value dependent on quality of the observed data

Multicompartment distribution

Varea > Vss > Vc

Two compartment model graph

use method of residuals to calculate C1

-use of back-extrapolation of the terminal phase slope will overestimate the volume of distribution

Varea, Vbeta, Vz

-volume calculated at the terminal elimination phase

-uses area under the concentration-time curve

-influenced by changes in clearance

-this is a method for calculation and does not mean that clearance is dependent on the volume of distribution

Volume of distribution at steady state, Vss

-not affected by clearance

-calculation using exponential parameters

Varea after extravascular administration

the dose that gains access to the systemic circulation might be less than 100%

Vd is time dependent during the...

distribution phase

How to identify Non-Linear PK

-systematic trends observed in dose normalized PK profile and NCA parameters with non-linear PK

-greater than dose-proportional increases in AUC with dose suggests saturable clearance mechanism

Intracellular catabolism

-following fluid phase endocytosis (non-specific)

-limited by interactions with FcRn

Target mediated elimination (specific)

-cell surface receptor: internalization

Soluble target: formation of large complexes - phagocytosis

Receptor mediated elimination

-may trigger endocytosis and catabolism

at extremely high doses, FcRn will be...

saturated

-dose dependent increases in CL

Soluble Target types

generally present in circulation (VEGF)

duration of therapy

-incidence typically increases with treatment time

Dose

ADA more frequently detected at lower does of mAb

Route of administration

ADA often found more frequently with SC/IM dosing

Biosimilars

biological product that his HIGHLY similar to and has NO clinically meaningful differences from an existing FDA approved reference product

If the drug is water soluble and not highly bound to plasma proteins, it can be...

directly eliminated

most drugs are too ______ to be directly eliminated

lipophilic

Phase 1 Metabolism

CYP enzymes; many phase I metabolites are active

Phase II Metabolism

phase II metabolites are usually water soluble and inactive

Drug elimination can only be measured in the clinic by analyzing...

changes in drug concentration over time in blood, urine, breath samples, etc.

volume of blood completely cleared of drug per unit time

considers entire body to be a single drug eliminating system made up of one or more elimination processes

-does not identify mechanism of elimination

What is the most useful measure of drug elimination and why?

Clearance; because it remains constant (it is NOT concentration dependent)

CL remains constant in the absence of...

1. drug interactions (enzyme induction/inhibition)

2. renal or hepatic dysfunction

3. certain diseases

- value does NOT change as we age

Compartmental (model-DEPENDENT) definition of CL

assumption - drug elimination is 1st order

-one compartment drug

-two compartment drug

Compartmental (model-INDEPENDENT) definition of CL

-one compartment

-multi compartment drug

Physiologic (non-compartmental model-independent) definition of CL

does not allow you to individualize your calculation of CL like def 1 and def 2

Extraction ratio

measures the efficiency of drug extraction (ranges from 0-1)

- when E=1, CL = blood flow

Low extraction

<0.3

Intermediate extraction

0.3-0.7

High extraction

>0.7

What is the use of CL in a clinical setting?

it can be used to calculate the patient's maintenance drug dose and any subsequent dosage adjustments

What is the 2-step approach to adjusting a drug dose?

1. calculate patient's CL

2. use CL to calculate new dose

As Km increases...

enzymes become saturated and it approaches its maximum rate

When Cul is low relative to enzyme concentration, it is what order?

first

What do we get when we divide velocity (rate) by Cu,L?

unbound metabolic clearance

What is the drug concentrations that are actually measured in practice?

peripheral venous drug concentrations

-not hepatic artery, portal vein, or hepatic vein bc it is too invasive

Characteristics associated with first-pass metabolism:

1. poor oral bioavailability (F)

2. greater patient-to-patient variability in F

3. Eh >0.7

Biliary exretion occurs by?

active transport

drug properties that favor biliary excretion

1. MW > 250

2. good water solubility

3. presence of a suitable carrier protein

What is enterohepatic cycling?

-biliary secretion dumps into small intestine

-excreted in feces unless reabsorbed from small intestine

-enterohepatic cycling = reabsorption of drug across small intestine

What metabolites are most often excreted in bile?

glucuronide conjugates

What is enterohepatic cycling promoted by?

action of beta-glucoronidase enzymes in the intestine

when Eh is high, what happens to Qh?

it is rate limiting

Do changes in fub or Clint affect hepatic clearance?

no

when Eh is low, what is rate-limiting?

Fub x CLint

Do changes in Qh have an effect on hepatic clearance?

nope

drugs that are normally greater than 80% protein bound may be affected by changes in ...

CLint or fub

As free fraction increases, what happens to the unbound plasma drug concentration?

it increases

As the free fraction increases, what happens to the total plasma drug concentration?

it increases

For must drugs the net result of 3 processes leads to renal drug elimination

1. glomerular filtration

2. renal tubular secretion (1 and 2 move drug from plasma into the renal tubule)

3. tubular reabsorption (moves drug from renal tubule back into the plasma)

Factors that can affect renal drug elimination

-plasma drug concentration (C)

-plasma binding (fub)

-renal blood flow (QR)

-urine flow rate

-urine pH

Drug properties that favor glomerular filtration

1. water solubility

2. molecular weight <500

3. low degree of plasma protein binding: rate of filtration = fub x C x GFR

Brush Border membrane

contains various organic anion (OA) transporters; the multidrug resistance transporter (MRP2) mediates primary active luminal secretion

Uptake of organic anions (OA) across basolateral membrane (BLM) is mediated by...

sodium dependent OAT transporters

Uptake of organic cations (OC) across BLM is mediated by...

organic cation transporters (OCT)

Luminal OC secretion across BBM is mediated by...

P-glycoprotein

Tubular secretion is possible ONLY if...

the drug has sufficient affinity for a carrier protein

When tubular secretion is highly efficient...

it becomes the primary mechanism of renal excretion

When tubular secretion is NOT efficient...

filtration is the primary mechanism of elimination

most drugs are reabsorbed by....

passive diffusion

variables that affect tubular reabsorption

1. urine flow rate (drug concentration gradient between renal tubule and plasma)

2. drug pKa - lipophilic (unionized) drugs are reabsorbed more efficiently than polar (ionized) drugs

3. urinary pH - ranges from 7.4 in the proximal tubule to 4.5 in the distal tubule

If CLr = fub x GFR

filtration is likely the ONLY mechanism of renal elimination

If CLr > fub x GFR

filtration and tubular secretion are BOTH occurring

if CLr < fub x GFR

filtration and tubular reabsorption are both occurring

Linear Pharmacokinetics

indicates that for a given individual and drug, all concentration-time profiles that are normalized for size of dose are superimposible

nonlinear pharmacokinetics

implies such profiles are not superimposable

Decrease in gut degradation or metabolism, mucosa degradation or metabolism or liver metabolism (first pass) leads to...

nonlinear bioavailability

Plasma Protein Binding

1. there are a limited number of binding sites to plasma proteins

2. get increased volume of distribution with saturable plasma protein binding

3. effect on total and free concentrations and clearance of drug depend on extraction ratio through liver

Tissue binding

1. binding sites can also be saturated

2. get decreased volume of distribution with saturable tissue binding sites

Saturable tubular secretion

secretion of organic anions and cations is a saturable, carrier mediated process located in the proximal tubular cells of the kidney

Glomerular filtration is a passive process and increases with...

drug concentration

reabsorption is USUALLY

passive and also increases with concentration

Secretion of organic anions and cations is a saturable, carrier mediated process located in...

the proximal tubular cells of the kidney. there are maximal capacities for tubular secretion

inhibit metabolism

increases Km