Ketoconazole with proton pump inhibitors

Loss of gastric acidity from chronic proton pump inhibitor treatment may affect the bioavailability of such drugs as ketoconazole, ampicillin esters, and iron salts. Chronic therapy, with proton pump inhibitors has been linked to increased frequency of hip fractures, possibly secondary to decreased absorption of calcium. 

Proton pump inhibitors cause a profound and long-lasting inhibition of gastric acid secretion therefore, proton pump inhibitors may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, ampicillin, iron salts, digoxin, cyanocobalamin). 

ITRACONAZOLE, KETOCONAZOLE PROTON PUMP INHIBITORS Possible i efficacy of the antifungal L absorption Monitor for i efficacy t dose may be required. Separate doses by at least 2 hours and give ketoconazole with a cola drink... 

Ketoconazole is water-soluble at a pH of below 3. Its oral absorption is influenced by the acidity of the stomach contents, and the concomitant administration of histamine H2 receptor antagonists, proton pump inhibitors, antacids, or food affects its absorption. A high carbohydrate meal ingested with ketoconazole reduces total drug absorption, while a high lipid meal increases it. Erratic absorption is particularly apparent in patients with AIDS. Peak serum concentrations are seen within 2-3 hours. The half-life is about 8 hours. CSF penetration is less than 10% (1). Ketoconazole is extensively metabolized in the liver and excreted in the bile in an inactive form less than 1% of the active drug is excreted in the urine. Clearance is not significantly altered by renal dialysis (1). 

Omeprazole is a proton pump inhibitor. Headache, skin rash, and diarrhea have all been recorded by adverse event registries sufficiently often to suggest causal relations (1). Omeprazole is a modest inhibitor of CYP isoforms. Interactions are less likely than with cimetidine and are probably of no practical importance. However, omeprazole reduces the absorption of drugs that require a low gastric pH (ketoconazole, iron salts, ampicilhn) and can inhibit the hepatic clearance of some drugs (diazepam, warfarin, phenytoin) (2). 

The interaction between itraconazole and omeprazole also appears to be established, but it appears that this can be minimised by using an oral itraconazole solution. As with ketoconazole, giving itraconazole with an acidic drink such as cola , (p.215) would minimise the interaction, and is recommended by some manufacturers of itraconazole for patients taking proton pump inhibitors. " Monitor patients taking itraconazole if proton pump inhibitors are also given. The effect of itraconazole on omeprazole is unknown, but it might be expeeted to increase omeprazole levels similarly to ketoconazole. 

An active substance, although initially released from its dosage form (and dissolved), may become unavailable for absorption due to reactimis with other medicines or food components [4]. An example is the formation of insoluble complexes of tetracycline with calcium or aluminium ions from antacids or milk products. Interaction (chelation or binding) with iron ions leads to a reduced absorption for a variety of active substances such as doxycycline, penicillamine, methyldopa and ciprofloxacin. The absorption of active substances showing pH-dependent dissolution behaviour may be influenced by medicines that influence the gastric pH, such as H2-antagonists, proton pump inhibitors and antacids. Antimycotic active substances such as ketoconazole or itraconazole dissolve better in acidic fluids. Therefore their bioavailability may be increased by the concomitant use of an acidic drink like cola, whereas the concomitant use of antacids or proton pump inhibitors is likely to reduce the bioavailability. Concomitant use of milk may increase the dissolution of acidic active substances, whereas fats from food may increase the bioavailability of lipophilic active substances like albendazole and griseofulvin. 

Following oral administration, approximately 75% of an administered ketoconazole dose is absorbed. However, there is considerable inter- and intrapatient variation, with oral absorption impaired when gastric acidity is decreased due to clinical pathology, e.g. achlorhydria, or due to concurrent administration of agents that decrease gastric acidity, e.g. antacids, H2-receptor antagonists or proton pump inhibitors, or whether the patient is in a fed or fasted state (absorption is enhanced in the fed state). 

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