Biomedical Engineering Reference
In-Depth Information
a quantitative structural activity relationship (QSAR) study indicated that
the anti-neoplastic activity was inversely proportional to the lipophilic-
ity. This is because the more lipophilic analogs become less soluble in the
aqueous plasma and bind more readily to plasma proteins, leading to lower
concentrations of the drug available for diffusion into the CNS, and dem-
onstrate diminished alkylating activity and increased dose limiting toxicity.
Hence, when a drug is delivered via the circulatory system for the treatment
of CNS diseases, a delicate balance between cerebro-vascular permeability
and plasma solubility is required.
The chemical delivery systems (CDS) require multiple chemical or enzy-
matic transformations prior to release of the active drug. The CDS are based
on a dihydropyridone-quaternary pyridinium ion redox system, which relies
on chemistry analogous to the ubiquitous NAD1-NADH coenzyme sys-
tem. The drug is converted into a 1,4-dihydropyridine moiety-containing
conjugate which is the CDS. Upon systemic administration in animals,
there is extensive tissue distribution with the conjugate accessing most of
the compartments, including the brain. The unstable dihydropyridine deriv-
ative is oxidized to form the hydrophilic polar quaternary pyridinium salt,
which is eliminated from most tissues but retained in the brain as a result
of the BBB, thus 'locking in' this ionized moiety. Subsequently, the carrier is
cleaved to provide the free active drug. A further approach for the delivery
of small molecules into the brain is to modify the drug so that mimics a
nutrient, thus giving it access to one of several specialized carrier-mediated
transport systems within the BBB. Essential compounds, such as amino ac-
ids, hexoses, vitamins and neuropeptides, normally need specific carriers to
permeate into the brain. Dopamine is not transported efficiently through
the BBB. Modification of dopamine to its neutral amino-acid precursor,
L-dopa, enhances brain uptake because of its affinity for the neutral amino-
acid transporter within the barrier.
Prodrugs are pharmacologically inactive compounds that result from
transient chemical modifications of biologically active species. The chemi-
cal change is usually designed to improve some deficient physicochemical
property, such as membrane permeability or water solubility. After adminis-
tration, the prodrug is brought closer to the receptor site and is maintained
there for longer periods of time. Here it is converted to the active form,
usually via a single activating step. Once in the CNS, hydrolysis of the modi-
fying group will release the active compound. Going to extremes on the li-
pophilic precursor scale, a possible choice for CNS prodrugs is coupling the
drug to a lipid moiety, such as fatty acid, glyceride or phospholipids. While
increased lipophilicity may improve movement across the BBB, it also tends
to increase uptake into other tissues, causing an increased tissue burden.
This selectivity in delivery is especially detrimental when potent drugs such
as steroids or cytotoxic agents are considered, since toxicity is exacerbated at
nontarget sites. Moreover, while increased lipophilicity may facilitate drug
