Page 86 - Basic _ Clinical Pharmacology ( PDFDrive )

72 SECTION I Basic Principles

the pharmacologic actions of anticoagulants and sedatives. The TABLE 4–7 Rapidly metabolized drugs whose
metabolism of the sedative chlordiazepoxide has been shown to be hepatic clearance is blood flow-limited.
inhibited by 63% after a single dose of cimetidine; such effects are
reversed within 48 hours after withdrawal of cimetidine. Alprenolol Lidocaine
Impaired metabolism may also result if a simultaneously admin- Amitriptyline Meperidine
istered drug irreversibly inactivates a common metabolizing enzyme. Clomethiazole Morphine
These inhibitors, in the course of their metabolism by cytochrome Desipramine Pentazocine
P450, inactivate the enzyme and result in impairment of their Imipramine Propoxyphene
own metabolism and that of other cosubstrates. This is the case of
the furanocoumarins in grapefruit juice, eg, 6′,7′-dihydroxyberga- Isoniazid Propranolol
mottin and bergamottin, which inactivate CYP3A4 in the intesti- Labetalol Verapamil
nal mucosa and consequently enhance its proteolytic degradation.
This impairment of intestinal first-pass CYP3A4-dependent flow-limited (Table 4–7). These drugs are so readily metabolized
metabolism significantly enhances the bioavailability of drugs by the liver that hepatic clearance is essentially equal to liver blood
such as ergotamine, felodipine, nifedipine, terfenadine, verapamil, flow. The impaired enzyme activity or defective formation of
ethinylestradiol, lovastatin, saquinavir, and cyclosporine A and is enzymes associated with heavy metal poisoning or porphyria also
associated with clinically relevant DDIs and food-drug interac- results in reduced hepatic drug metabolism. Pulmonary disease
tions. The list of drugs subject to DDIs involving grapefruit juice may also affect drug metabolism, as indicated by the impaired
is extensive and includes many drugs with a very narrow therapeu- hydrolysis of procainamide and procaine in patients with chronic
tic index and a high potential for lethal adverse reactions. How- respiratory insufficiency and the increased half-life of antipyrine (a
ever, it must be borne in mind that not all commercially available P450 functional probe) in patients with lung cancer.
grapefruit juices are equally potent, as the CYP3A4 inactivation Although the effects of endocrine dysfunction on drug metabo-
potency is totally dependent on the amount of furanocoumarins lism have been well explored in experimental animal models, cor-
extracted into the juice from the zest (highest), pith, and pulp of responding data for humans with endocrine disorders are scanty.
the grapefruit. Furthermore, recovery from these interactions is Thyroid dysfunction has been associated with altered metabolism of
dependent on CYP3A4 resynthesis and thus may be slow. some drugs and of some endogenous compounds as well. Hypothy-
roidism increases the half-life of antipyrine, digoxin, methimazole,
Interactions between Drugs & and some β blockers, whereas hyperthyroidism has the opposite
Endogenous Compounds effect. A few clinical studies in diabetic patients indicate no appar-
ent impairment of drug metabolism, although impairment has been
Some drugs require conjugation with endogenous substrates such as noted in diabetic rats. Malfunctions of the pituitary, adrenal cortex,
GSH, glucuronic acid, or sulfate for their inactivation. Consequently, and gonads markedly reduce hepatic drug metabolism in rats. On
different drugs may compete for the same endogenous substrates, the basis of these findings, it may be supposed that such disorders
and the faster-reacting drug may effectively deplete endogenous sub- could significantly affect drug metabolism in humans. However,
strate levels and impair the metabolism of the slower-reacting drug. until sufficient evidence is obtained from clinical studies in patients,
If the latter has a steep dose-response curve or a narrow margin of such extrapolations must be considered tentative.
safety, potentiation of its therapeutic and toxic effects may result. Finally, the release of inflammatory mediators, cytokines, and
nitric oxide associated with bacterial or viral infections, cancer, or
Diseases Affecting Drug Metabolism inflammation are known to impair drug metabolism by inactivat-
ing P450s and enhancing their degradation.
Acute or chronic diseases that affect liver architecture or function
markedly affect hepatic metabolism of some drugs. Such condi- REFERENCES
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