Show Summary Details
Page of

Absorption, distribution, metabolism, and excretion 

Absorption, distribution, metabolism, and excretion
Chapter:
Absorption, distribution, metabolism, and excretion
Author(s):

Adrian Kilcoyne

, Daniel O’Connor

, and Phil Ambery

DOI:
10.1093/med/9780199609147.003.0036
Page of

PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). © Oxford University Press, 2015. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy).

Subscriber: null; date: 16 October 2017

Overview

ADME stands for absorption, distribution, metabolism, and excretion, the 4 key processes that underlie pharmacokinetics. Pathophysiological disorders that affect any stage of this process, and characteristics of a medicine that affect any or multiple stages of this process can impact on the time concentration curve of the medicine and, thus, efficacy and toxicity.

Examples of the impact of the components of ADME and how they may impact on the development process are described below.

Absorption

For oral drugs, absorption is the extent to which a drug is absorbed from the gut lumen into the portal circulation. Two important features are the rate and extent of absorption. Examples of factors governing drug absorption from the gastrointestinal (GI) tract are shown in Table 3.1.1.

Table 3.1.1 Examples of factors governing drug absorption from the GI tract

Better absorption

Worse absorption

Low molecular weight

High molecular weight

Polar (acidic or basic)

Neutral

Examples of methods of delivery are shown in Table 3.1.2.

Table 3.1.2 Methods of delivery

Route

Example substance

Oral

Digoxin—low molecular weight, polar substance, well absorbed

Oral

Bisphosphonates—very high molecular weight, very poorly absorbed, low bioavailability

Transdermal

Testosterone patch—sustained delivery allows for gradual release of testosterone, preferable to injections

Pulmonary

Insulin—subject to degradation by stomach enzymes, insulin efficiently absorbed by respiratory mucosa

Distribution

Distribution refers to the process of the drug moving into and out of the tissues of the body. The volume of distribution relates the concentration of the drug in the plasma to the total amount of the drug in the body. Examples of factors that may impact on volume of distribution are shown in Table 3.1.3.

Table 3.1.3 Factors that may impact on volume of distribution (examples)

Low volume of distribution

Large volume of distribution

Highly protein bound

Low protein binding

Low level of lipophilicity

Highly lipophilic (increased tissue binding)

Metabolism

Metabolism describes the processes (biotransformation) that change the drug into another molecule. In general these processes can be classified as Phase I and Phase II reactions. The liver is the principal organ of drug metabolism. Many examples exist that impact as CYP-450 enzyme inhibitors or inducers, leading to reduced or increased drug concentrations. Four examples are detailed in Table 3.1.4. A fuller list of the main CYP-450 inhibitors/inducers can be found at the online version of the P450 Drug Interaction Table.

Table 3.1.4 Examples of CYP-450 enzyme inhibitors or inducers

Drug/class

Inhibitor/inducer

Macrolide—erythromycin, clarithromycin

CYP-450 3A4 inhibitors

Fruit juices (cranberry/grapefruit)

Inhibitors of CYP-2C8 / CYP 3A4

Herbal antidepressant (St John’s Wort)

CYP-450 enzyme inducer

Carbamazepine

CYP-450 enzyme inducer

Excretion

Excretion describes the processes that remove the drug from the body. A number of routes for drug excretion exist. Examples are given in Table 3.1.5.

Table 3.1.5 Example routes for drug excretion

Route

Example

Hepatic

Pancuronium

Pulmonary

Enfluorane

Renal—Passive filtration

Digoxin

Renal—anionic active transporter

Oseltamivir

Renal—cationic active transporter

Famotidine

Renal transport inhibitor

Dapafloglozin—SGLT-2 inhibitor

Each aspect of pharmacokinetic (PK) is important in clinical development and we explore each aspect of ADME in pre-clinical and clinical development.