Tetracyclines Foods: Milk

The oral dosage for rapidly excreted tetracyclines, equivalent to tetracycline hydrochloride, is 0.25-0.5 g four times daily for adults and 20-40 mg/kg/d for children (8 years of age and older). For severe systemic infections, the higher dosage is indicated, at least for the first few days. The daily dose is 600 mg for demeclocycline or methacycline, 100 mg once or twice daily for doxycycline, and 100 mg twice daily for minocycline. Doxycycline is the oral tetracycline of choice because it can be given as a once-daily dose and its absorption is not significantly affected by food. All tetracyclines chelate with metals, and none should be orally administered with milk, antacids, or ferrous sulfate. To avoid deposition in growing bones or teeth, tetracyclines should be avoided in pregnant women and children less than 8 years of age. 

Do not give food, milk, or other daily products for 1 hour before or 2 hours after tetracyclines are administered. 

Concomitant use of tetracycline with antacids containing aluminum, calcium, or magnesium decreases absorption of oxytetracycline (because of chelation) concomitant use with food, milk or other dairy products, oral iron products, or sodium bicarbonate also impairs oral absorption. 

Leyden JJ. Absorption of minocycline hydrochloride and tetracycline hydrochloride. Effect of food, milk, and iron. J Am Acad Dermatol (1985) 12,308-12. 

Tetracyclines. It is important to give the tetracyclines on an empty stomach tetracyclines are not to be taken with dairy products (milk or cheese). The exceptions are doxycycline (Vibramycin) and minocycline (Minocin), which may be taken with dairy products or food. The nurse should give clindamycin with food or a full glass of water. The nurse can give troleandomycin and clarithromycin without regard to meals. All tetracyclines should be given with a full glass of water (240 mL). 

A number of methods have been described for determination of tetracycline (chlortetracycline, tetracycline, and oxytetracycline) residues in tissues of food-producing animals (53-62), fish (63), eggs (64), and honey (65,66). Most of these methods use reversed-phase HPLC for determination. However, one uses TLC with UV densitometry ( ) and one uses GLC ( ), and one uses a direct mass spectrometric method CAD MIKE spectrometry (collisionally activated decomposition mass-analyzed ion kinetic spectrometry) for oxytetracycline in milk and meat (62). Several use solid-phase extraction in the cleanup procedure using XAD-2 resin (56,58) or Cj g cartridges... 

We have already met several of the important concepts in this topic, so now it is time to round them up and bring out the major principles. In the first place drug molecules clearly might interact with food molecules in the lumen of the gut. Perhaps the best-known example of this is the interaction between the tetracyclines and dietary calcium and iron. The binding, which occurs between them, produces a chelate, which is not particularly lipid-soluble, and therefore the overall absorption of tetracycline may be reduced to the point where plasma levels do not achieve effective antibiotic concentrations. The commonest dietary constituent to produce this binding is milk with its high calcium content. Tetracycline ingestion should be separated from food as far as possible. 

These antibiotics are partially absorbed from the stomach and upper gastrointestinal tract. Food impairs absorption of all tetracyclines except doxycycline and minocycline. Absorption of doxycycline and minocy-cbne is improved with food. Since the tetracyclines form insoluble chelates with calcium (such as are found in many antacids), magnesium, and other metal ions, their simultaneous administration with milk (calcium), magnesium hydroxide, aluminum hydroxide, or iron will interfere with absorption. Because some of the tetracyclines are not completely absorbed, any drug remaining in the intestine may inhibit sensitive intestinal microorganisms and alter the normal intestinal flora. 

The absorption of tetracycline administered orally is variable and depend upon the type of tetracycline used. The tetracycline form insoluble complexes i.e. chelation with calcium, magnesium, milk and antacids reduce their absorption. Administration of iron also interferes with the absorption of tetracycline. Doxycycline is rapidly and virtually completely absorbed after oral administration and its absorption is not affected by presence of food or milk. 

In food-producing animals, tetracyclines can be administered orally through feed or drinking water, parenterally, or by intramammary infusion. However, oral administration suppresses initially die ruminal fermentation of plant fiber. The absorption of tetracyclines can be further adversely affected by the presence of metallic ions in the gastrointestinal tract. All tetracyclines have an affinity for metallic ions and should not be administered with milk or high calcium levels in feed unless an upward adjustment in the dosage is made (226-228). 

WA Moats, R Harik-khan. Rapid HPLC determination of tetracycline antibiotics in milk. J Agr Food Chem 43 931-934, 1995. 

S Taguchi, S Yoshida, S Fukushima, S Hori. Rapid determination of tetracycline antibiotics in milk by HPLC using an on-line clean-up system. J Food Hygienic Society Japan 38 259-64, 1997. 

Carlsson, A., Bjorck, L. 1992. Liquid chromatography verification of tetracycline residues in milk and influence of milk fat lipolysis on the detection of antibiotic residues by microbial assays and the Charm II test. J. Food Prot. 55, 374-378. 

Milk and dairy foods decrease the absorption of some tetracyclines (doxycycline and minocycline are not affected), some quinolone antibiotics (absorption of ciprofloxacin and norfloxacin is decreased but ofloxacin is not affected), penicillamine and alendronate. Large volumes of milk can reduce the ulcer-healing properties of bismuth tripotassium dicitratobismuthate (bismuth chelate),... 

The presence of food in the stomach, especially if it is fatty, delays gastric emptying and the absorption of certain dmgs the plasma concentration of ampicillin and rifampicin may be much reduced if they are taken on a full stomach. More specifically, calcium, e.g. in milk, interferes with absorption of tetracyclines and iron (by chelation). 

The early tetracyclines, particularly TC, exhibited erratic oral absorption. In some instances this was later related to dosage formulations where purportedly inert fillers were found to contain divalent cations such as Mg2+ and Ca2+, which are now known to chelate the drug and actually decrease solubility so would administration of calcium-containing products (milk, antacids) or iron preparations. Foods can generally interfere with the efficient absorption of the earlier tetracyclines. This effect appears to be much less significant with the newer agents such as DC and MNC. Even when taken on an empty stomach, TC and OTC have a much slower absorption rate, with blood levels not reaching maxima for 4 hours, whereas DC and MNC attain it within 2 hours. 

Tetracycline is produced by fermentation of Streptomyces aureofaciens and related species or by catalytic reduction of chlortetracycline. The blood levels achieved on oral administration often are irregular. Food and milk lower absorption by approximately 50%. 

Demeclocycline lacks the C-6-methyl of tetracycline and is produced by a genetically altered strain of Streptomyces aureofaciens. Because it is a secondary alcohol, it is more chemically stable than tetracycline against dehydration. Food and milk co-consumption decrease absorption by half, although it is 60 to 80% absorbed by fasting adults. It is the tetracycline most highly associated with phototoxicity and has been shown to produce dose-dependent, reversible diabetes insipidus with extended use. 

It is produced by semisynthesis from other tetracycline molecules and is the most widely used of the tetracycline family. Doxycycline is well absorbed on oral administration (90-100% when fasting reduced by 20% by co-consumption with food or milk), has a half-life permitting once-a-day dosing for mild infections, and is excreted partly in the feces and partly in the urine. 

Give tetracycline 1-3 hours before or after giving the patient antacids, calcium supplements, choline and magnesium salicylates, iron supplements, magnesium salicylate, or magnesium laxatives, foods containing milk and milk products. These lower the absorption of tetracycline. 

A 2008 paper has described for the first time a dilute and shoot strategy for the simultaneous extraction of wide variety of residues and contaminants (pesticides, myco-toxins, plant toxins, and veterinary drugs) from different foods (meat, milk, honey, and eggs) and feed matrices. Several antimicrobial classes were included (sulfonamides, quinolones, P-lactams, macrolides, ionophores, tetracyclines, and nitroimidazoles) in the analytical method. Sample extraction was performed with water/acetonitrile or acetone/1% formic acid, but instead of dilution of the extracts before analysis by UPLC-MS/MS, small extract volumes (typically 5 til) were injected to minimize matrix effects. Despite the absence of clean-up steps and the inherent complexity of the different sample matrices, adequate recoveries were obtained for the majority of the ana-lyte/matrix combinations (typical values for antimicrobials were in the range of 70-120%). In addition, the use of UPLC allows high-speed analysis, since all analytes eluted within 9 min. 

Eritz J, Zuo Y, Simultaneous determination of tetracycline, oxytetracycline, and 4-epitetracycline in milk by high performance liquid chromatography. Food Chem. 2007 107 1297-1301. 

Tetracycline forms insoluble complexes with calcium ions. Absorption of these antibiotics is substantially reduced if they are taken with milk, certain food or other sources of calcium such as some antacids. In the past, the incorporation of dicalcium phosphate as a filler in tetracycline dosage forms also reduced its bioavailability. 

There seem to be no direct clinical studies with calcium-containing antacids, but a clinically important interaction seems almost a certainty, based on in vitro studies with calcium carbonate, calcium in milk, (see Tetracyclines + Food or Drinks , p.347), dicalcium phosphate, and calcium as an excipient in tetracycline capsules. 

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. 

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