Clearance by each organ (liver, kidneys) depends on the blood flow rate to the organ

as well as the extraction ratio. Total body clearance is composed of the sum of

individual organ clearances. Another significant parameter to be considered in drug

metabolism is half-life (t1/2). It is defined as the time taken to reach one-half of the

original amounts of drug in the body or plasma level. Drug’s half-life depends on Vd

and CL. Since the age-related change in Vd is relatively small, mostly the CL

reduction is seen with ageing, resulting in prolonged half-life of a drug in geriatric

patients. Usually, it takes longer period for the drug to reach steady-state as well as

longer interval for elimination in frail and elderly. Thus, dosing schedules and drug

amounts must be carefully monitored to adjust dosages in elderly patients to avoid

ADRs (Hilmer 2008). Liver is the major xenobiotic metabolizing organ in humans

and many other species. For hepatic clearance (CLh), the portal and arterial hepatic

blood flow play a key role in determining the systemic exposure to drugs and

metabolites. Aging leads to a number of significant changes in the liver, including

reduction in size, blood flow, drug-metabolizing enzyme capacity and development

of pseudo-capillaries. Several other factors like comorbidity, concomitant medica-

tion, frailty, and epigenetics can also influence hepatic clearance of drugs. Generally,

hepatic blood flow is reduced by approx. 40% in old age with a corresponding

reduction in clearance of highly extracted substrates, such as morphine, propranolol,

verapamil, and amitriptyline (McLean and Le Couteur 2004). Hence, age-related

changes in the liver not only cause decrease in the hepatic clearance of unbound

drug, but also influence the pharmacological response to medicines in older people.

Ageing may affect both phase I (hepatic metabolism by CYP450 coenzymes) and

phase II metabolism (glucuronidation, sulfation, GSH-conjugation, etc.). The

age-related clearance would be especially affected for drugs that undergo mandatory

oxidation (dealkylation, hydroxylation, deamination) by the microsomal cytochrome

P450-dependent mono-oxygenase systems. Since liver volume and blood flow

decline with age, partly due to the impaired regeneration capacity, the diminished

clearance would most likely occur for drugs that exhibit first-pass kinetic profiles

(Schmucker 2001).

15.8

Excretion

Kidneys are the major organs for excretion of unchanged drug and/or metabolites via

glomerular filtration, tubular secretion, and tubular reabsorption. A gradual decline

in the renal function with advancing age reduces the excretory capacity of the

kidneys. Hence, in order to assess the excretion of xenobiotics and their metabolites,

evaluation of blood flow levels and renal function become crucial parameters to

determine the glomerular filtration rate (GFR). Irrespective of intestinal absorptive

defects, creatinine clearance and decline in urinary D-xylose excretion account for

the reduction in renal clearance (Russell 2001). One of the major contributing factor

to reduced metabolic disposition of drugs in old age may be decreased tissue

perfusion, particularly to less perfused organ/tissue such as skeletal muscle (Payne

and Bearden 2006), and fat tissue (Nnodim 1988). One of the most important

242

M. Bhaskar et al.