tissue-binding properties, and transporters. Depending on the plasma protein bind-

ing, drugs can have small Vd (e.g., heparin and warfarin) or large Vd (e.g.,

risedronate). A typical incremental decrease in albumin and increase in α1-acid

glycoprotein levels in elderly are unlikely to have large effects on drug distribution.

But transmembrane protein may alter with aging. Extracellular space of the central

nervous system (CNS), which is guarded by the blood-brain barrier (BBB) from

non-selective crossing of xenobiotics, is a special compartment from the pharmaco-

logical point of view. The BBB impairment can affect drug disruption process in the

CNS, which is generally associated with neurodegenerative disorders (memory loss

and cognition) among the elderly. Besides the morphological alterations of the

cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal

elements), the BBB changes also occur at the molecular level (tight junction

proteins, adheres junction proteins, membrane transporters, basal lamina, extracel-

lular matrix), and these pathologies are the major contributors to the onset and

progression of neurological disorders. One of the most important transporters at

the BBB is the multidrug transport protein P-glycoprotein (P-gp), encoded by

MDR1/ABCB1 and belonging to the family of ATP binding cassette (ABC)

transporters. P-gp is highly expressed at the BBB vessel walls of the brain

capillaries, where it functions as an efflux pump to restrict the entry/distribution of

many different drug moieties from blood to the brain. van Assema et al. (2012) have

reported an age-associated decline in the expression and function of ABCB1

transporters at the BBB through PET studies. This evidence was further extended

by Bauer et al. (2017), confirming that an age-associated reduction occurring in

ABCB1 expression and function at the BBB leads to higher increase in the brain

distribution of ABCB1-selective substrates like (R)-[¹¹C]-verapamil when ABCB1

is partially inhibited, viz., after the consumption of polyphenolic plant-derived fresh

foods. But this could result in an elevated risk of ABCB1-mediated drug-drug

interactions (DDIs) at the BBB in elderly persons, which may have important

adverse consequences for pharmacotherapy in patients of advanced age. Antidepres-

sant compounds need to penetrate the BBB to reach the site of action within the

brain; therefore, inhibition of P-gp transport proteins can have marked impact on the

efficacy of antidepressant drugs (O’Brian et al. 2011). Currently, CYP-450

genotyping pilot studies are being conducted to map clinical feasibility of

transport-protein genotyping. Thus, the ABCB1-guided antidepressant treatment

strategy is not a dream anymore (Zeier et al. 2018).

15.7

Metabolism

Metabolism involves the biodegradation of drug molecules, mainly by hepatic

cytochrome 450 coenzymes, to be transformed into more polar and water-soluble

compounds ready for clearance into the bile, feces, and kidney. Clearance (CL) is

defined as an elimination rate constant (ke) relating to the rate of elimination of a

drug from the body and/or the plasma clearance (Cpl). It determines the maintenance

dose required to keep optimal therapeutic drug concentration in the plasma.

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The Importance of Drug Dose Adjustment in Elderly Patients with Special. . .

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