| Absorption and Distribution: |
| The imidazoles are rapidly but sometimes erratically absorbed from the GI tract; plasma levels peak within 2 hr after administration PO. Fluconazole is an exception, being close to 100% bioavailable after administration PO. Except for fluconazole, an acidic environment is required for the dissolution of the imidazoles, and a decrease in gastric acidity can reduce the bioavailability after administration PO. The rate of absorption appears to be increased when the drug is given
with meals, but reports are conflicting. |
| Imidazoles appear to be widely distributed in the body with detectable concentrations in saliva, milk, and cerumen. CSF penetration is poor except for fluconazole, which reaches 50-90% of plasma concentrations. Most imidazoles (except fluconazole) are highly protein bound in the circulation (>95%), most to albumin. The highest concentrations of imidazoles are found in the liver, adrenal glands, lungs, and kidneys. |
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| Biotransformation and Excretion: |
| Hepatic metabolism is the primary route of elimination. Metabolism of ketoconazole and most other imidazoles by oxidative pathways is extensive. Only ~2-4% of a dose administered PO appears unchanged in the urine. Itraconazole is metabolized to an active metabolite that may contribute significantly to antimicrobial activity. The biliary route is the major excretory pathway (>80%); ~20% of the metabolites are eliminated in the urine. Fluconazole (in people) is eliminated
(≥90%) unchanged in the urine. |
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| Pharmacokinetics: |
| The rate of elimination of ketoconazole appears to be dose dependent—the greater the dose, the longer the elimination half-life. There is also a biphasic elimination pattern with rapid elimination in the first 1-2 hr, then a slower decline over the next 6-9 hr. Ketoconazole is usually administered bid . The half-life of itraconazole is longer (up to 48 hr in cats), thus allowing treatment sid-bid. Because of the long half-life and mechanism
of action (impaired synthesis of the fungal cell membrane), time to efficacy may take longer than drugs that have more rapid actions (such as amphotericin B). |
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