Drugs will not always be uniformly distributed to and retained by body tissues. The concentrations of some drugs will be either considerably higher or considerably lower in particular tissues than could be predicted on the basis of simple distribution assumptions. This observation is demonstrated in the following examples:
1. Kidney. Since the kidneys receive 20 to 25% of the cardiac output, they will be exposed to a relatively large amount of any systemically administered drug. The kidney also contains a protein, metallothionein, that has a high affinity for metals. This protein is responsible for the renal accumulation of cadmium, lead, and mercury.
2. Eye. Several drugs have an affinity for the retinal pigment melanin and thus may accumulate in the eye. Chlorpromazine and other phe-nothiazines bind to melanin and accumulate in the uveal tract, where they may cause retino-toxicity. Chloroquine concentration in the eye can be approximately 100 times that found in the liver.
3. Fat. Drugs with extremely high lipid-water partition coefficients have a tendency to accumulate in body fat. However, since blood flow to adipose tissue is low (about 3 mL/100 g/minute), distribution into body fat occurs slowly. Drug accumulation in body fat may result either in decreased therapeutic activity owing to the drug's removal from the circulation or in prolonged activity when only low levels of the drug are needed to produce therapeutic effects. In the latter instance, fat depots provide a slow, sustained release of the active drug. Should body fat be seriously reduced, as during starvation, stored compounds
(e.g., DDT and chlordane) may be mobilized, and toxic symptoms may ensue.
4. Lung. The lung receives the entire cardiac output; therefore, drug distribution into it is very rapid. Most compounds that accumulate in the lung are basic amines (e.g., antihistamines, imipramine, amphetamine, methadone, phen-termine, chlorphentermine, and chlorpro-mazine) with large lipophilic groups and pK values greater than 8. However, some nonbasic amines, such as the herbicide paraquat, also can accumulate in the lung.
5. Bone. Although bone is a relatively inert tissue, it can accumulate such substances as tetracy-clines, lead, strontium, and the antitumor agent cisplatin. These substances may accumulate in bone by absorption onto the bone crystal surface and eventually be incorporated into the crystal lattice. Tetracycline deposition during odontogenesis may lead to a permanent yellow-brown discoloration of teeth, dysplasia, and poor bone development. Lead can substitute for calcium in the bone crystal lattice, resulting in bone brittleness. Bone may become a reservoir for the slow release of toxic substances, such as lead and cisplatin.
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