Tetracycline

Limits on what this shows

• Null findings: The comparison group, on three unrelated drugs, showed no fall [14]. No study showing unchanged vitamin C after tetracycline was found, and none showing clinical scurvy.
• At-risk subgroups: Elderly men were the only group studied; baseline vitamin C status, diet and illness were not in the abstract. Older and acutely ill people commonly have low leucocyte vitamin C regardless of drug, so the study cannot show how general the finding is.

Regulatory status

Neither label read mentions vitamin C or ascorbic acid [1][2][3].

Population evidence

Windsor, Hobbs, Treby and Cowper 1972 [14] (Br Med J 1:214-215; PubMed record, and the open-access BMJ PDF opened this revision through a summarizing fetch): 14 men aged 73 to 94 "showed a fall in leucocyte ascorbic acid levels during five days' treatment with 1 g of tetracycline daily." Per the full-text summary the dose was 250 mg four times daily, leucocyte ascorbic acid was measured daily before, during and after treatment (Denson and Bowers method), the fall occurred in all 14 men, was visible by day 4 and reached at least 50% below pretreatment values; the volunteers were on a normal ward diet without vitamin supplements or citrus fruit and had no clinical signs of deficiency. The text gives no numeric values or p-values (figures show means and ranges). Comparison group: nine men aged 74 to 90 who showed no fall; three each took phenobarbitone 60 mg three times daily, phenylbutazone 200 mg three times daily or aloxiprin 1,200 mg four times daily. Two further men aged 87 and 90 on the same dose showed increased urinary ascorbic acid excretion while leucocyte levels fell. The study was funded by Roche Products Ltd. The authors cite Shah 1968 as showing ascorbic acid depletion in buffy coat and serum on tetracycline (a secondary statement; Shah itself could not be opened). A second record, Shah, Barbhaiya and Srinivasan 1968 [15] (J Indian Med Assoc 51:127-129, "Ascorbic acid levels in blood during tetracycline administration"; MeSH: ascorbic acid/blood, humans, leukocytes/drug effects), was opened but has no abstract, so its direction and size are unknown. A third record (Ajmani, Sarin, Gupta and Chuttani 1971, Indian J Med Res 59:1610-1611, "Utility of ascorbic acid in tetracycline therapy", PMID 5158998) was opened as a PubMed record: it is typed a comparative study, has no abstract, and no ascorbic acid level measurement can be inferred, so it is not used. Ringsdorf 1980 (J Oral Med, "Vitamin C and antibiotics", PMID 6929321) has no abstract in PubMed or OpenAlex and is not used [35]. OpenAlex and PubMed lookups for a second independent cohort with the same measurement found none.

Mechanism

Not tested. The Windsor authors propose blocked renal tubular reabsorption of ascorbic acid (the increased urinary excretion in two men fits this), catalysis of ascorbic acid oxidation to dehydroascorbic acid, and a link to impaired phagocytosis; these are discussion points, not measured mechanisms [14].

Counter-evidence held on record

Counter-evidence and confounding Small sample, a 1972 short report, manufacturer funding, no placebo (the comparison men were on other active drugs), and no numeric values reported in the text. Leucocyte ascorbate falls with acute illness and age. The entry is a functional tissue marker, not a plasma deficit or a clinical outcome. Why not red One opened primary cohort with a confirmed direction and a large relative fall; the second human record (Shah 1968) could not be opened beyond the secondary mention in Windsor, so no second independent Tier A source was verified; no tested mechanism; no numeric values. Framing caution This is a bounded observation from one small, old study. It is not a vitamin C deficiency, not scurvy, and not a basis to recommend vitamin C supplementation with tetracycline.

Limits on what this shows

• Null findings: Wiesner's table row for iron(III)-hydroxide polymaltose complex found no significant AUC difference [6]. No human study read measured calcium or magnesium status after tetracycline; the bone-complex statement in the label concerns tissue binding.
• At-risk subgroups: People taking daily iron, mineral multivitamins, antacids, sodium bicarbonate or dairy with tetracycline. Not defined further by any source read.

Regulatory status

Labels: absorption of tetracyclines is impaired by antacids containing aluminum, calcium or magnesium and by preparations containing iron, zinc or sodium bicarbonate; the Chartwell label adds "Food and some dairy products also interfere with absorption" [1][2][3]. No numeric effect or interval appears in the text retrieved.

Population evidence

Wiesner 2024 [6] (systematic review with meta-analyses; plain tetracycline in the quantitative synthesis for food only): 5 non-randomized longitudinal studies, 38 participants; AUC ratio 0.60 (95% CI 0.50 to 0.73), about 40% lower in the fed state (range 27% to 50%), I-squared 64%; Cmax ratio 0.63 (0.54 to 0.74), I-squared 58%; Tmax longer by 0.54 h (0.04 to 1.03). The review rates evidence quality low. In its qualitative Table 4, the tetracycline AUC row for "antacid, mineral supplement" read "AUC down 31% to 90% with aluminium magnesium hydroxide and other iron supplements" (the page was truncated mid-table, so the rest of the row, milk, calcium and zinc rows were not seen). Leyden 1985 [7] (PubMed abstract via summarizing fetch): two groups of 8 volunteers; tetracycline absorption was inhibited 81% by 300 mg ferrous sulfate, 65% by milk and 46% by food. Neuvonen 1970 [8] (abstract only): ferrous sulphate markedly reduced absorption of tetracycline and three derivatives. Neuvonen and Turakka 1974 [9]: double-blind crossover in 6 volunteers, 500 mg tetracycline with 40 mg elemental iron as six different iron salts; ferrous sulphate inhibited most and ferric sodium edetate least (rank order only in the abstract).

Mechanism

Present: divalent and trivalent cations chelate tetracyclines in the gut lumen to form poorly absorbed complexes (label statement [1][2]). Brion-series chemistry names tetracycline among the tetracyclines forming calcium and magnesium complexes, including mixed calcium-magnesium ternary species, and models the metal-bound fraction as more than 99% of drug in plasma (Berthon 1983, four tetracyclines including tetracycline) [29]. These are in vitro and simulation papers, read as PubMed abstracts through a summarizing fetch.

Counter-evidence held on record

Counter-evidence and confounding The studies are small, old and non-randomized, and the Leyden, Neuvonen and Wiesner data may overlap, so they are not independent confirmations of each other. Framing caution Direction is mineral to drug. Do not read this as tetracycline lowering calcium, magnesium or aluminum, and do not add minerals. The action is timing; a prescriber or pharmacist decides any interval.

Limits on what this shows

• Null findings: The simulation's own plasma conclusion is null [29]. No human study of serum or urinary zinc during tetracycline therapy was located.
• At-risk subgroups: Not defined. Co-ingestion of zinc products is a timing issue per the label.

Regulatory status

Labels list preparations containing zinc as impairing tetracycline absorption [1][2][3]; no statement that tetracycline lowers zinc.

Population evidence

Penttila, Hurme and Neuvonen 1975 [10] (Eur J Clin Pharmacol 9:131-134; abstract via summarizing fetch): crossover in 7 volunteers, zinc sulphate 45 mg Zn given with tetracycline hydrochloride 500 mg; serum concentration, AUC and urinary excretion of tetracycline were each reduced by about 30% (p<0.05); doxycycline was not significantly affected; the authors judged the clinical significance probably limited. Brion, Lambs and Berthon 1985 [29] (Agents Actions 17:229-242; PubMed abstract via summarizing fetch): zinc complex formation constants for six tetracyclines including tetracycline at 37 degrees C in a simulated plasma medium; "No significant effect can be expected from tetracyclines on the distribution of zinc in plasma"; in gastrointestinal fluid zinc-tetracycline interactions strongly affect the bioavailability of both zinc and the antibiotic. Numeric constants and the full text were not retrieved.

Mechanism

Present as chemistry: chelation of zinc by tetracycline in the gut lumen (mechanism class A). Whether gut-lumen complexation changes body zinc in people on a standard course was not tested in any source read.

Counter-evidence held on record

Counter-evidence and confounding A 1985 simulation depends on assumed inputs and was read as an abstract. The 7-volunteer study [10] measured drug, not zinc. Framing caution Not a zinc deficiency claim and not a claim that tetracycline lowers body zinc. No zinc supplementation is implied.

Limits on what this shows

• Null findings: Tetracycline hydrochloride itself did not cause renal changes in the rat and dog experiments [23]. No Fanconi syndrome statement was found in the labels read.
• At-risk subgroups: Anyone taking expired, heat-exposed or improperly stored product; children were among the reported cases [22].

Regulatory status

The two labels read, and the Drugs.com copy of a capsule label, contain no Fanconi or outdated-drug statement (checked for the terms Fanconi, outdated, degraded and expired in the summaries; absence in a summary is not proof of absence in the label) [1][2][3].

Population evidence

Frimpter 1963 [22] (JAMA 184:111; abstract reconstructed by OpenAlex): three patients, each of whom had taken deteriorated tetracycline, developed nausea, vomiting, proteinuria, acidosis, glycosuria and aminoaciduria, first resembling diabetes mellitus; all recovered within about a month; the author concluded a degradation product, probably epi-anhydrotetracycline or anhydrotetracycline, was the cause. Fulop and Drapkin 1965 (NEJM 272:986-989; PubMed record opened, no abstract) is titled "Potassium-depletion syndrome secondary to nephropathy apparently caused by outdated tetracycline", with MeSH hypokalemia and potassium deficiency [25]. Montoliu 1981 (BMJ 283:1576-1577; PubMed record opened, no abstract) is a case report titled "Lactic acidosis and Fanconi's syndrome due to degraded tetracycline" [25]. A PubMed listing for tetracycline and Fanconi syndrome (28 results, first 10 seen) also showed Gross 1963 (Ann Intern Med), Cleveland 1965 (J Pediatr), Rice 1964, Varavithya 1971 and Escuin Sancho 1981, all titled as degraded or outdated tetracycline, not opened [25]. Serum and urine phosphate values, bicarbonate values and sample details beyond Frimpter's three patients were not retrievable; phosphate wasting is therefore inferred from the syndrome name, not from a number I read. A 2009 review (Zietse, Nat Rev Nephrol) states that toxic effects of tetracyclines can produce complete proximal tubular dysfunction and cites Montoliu [24].

Mechanism

Present, animal-supported: in rats (72, single 1,000 mg/kg oral doses) and dogs (3, intravenous), only anhydro-4-epi-tetracycline produced proteinuria, glucosuria, urinary enzyme release and proximal tubular necrosis, while tetracycline hydrochloride itself did not [23]. Phosphate, potassium and bicarbonate were not measured in that paper.

Counter-evidence held on record

Counter-evidence and confounding Case reports are Tier B and cannot estimate frequency; the exposure is an out-of-date product, a quality problem. Hard Rule 2: tubular toxicity is not a nutrient deficiency; the electrolyte losses are a downstream effect of renal injury. Framing caution This is not a finding that tetracycline taken as dispensed depletes phosphate, potassium or bicarbonate, and it does not call for any supplement. The only action is not to use outdated product.

Limits on what this shows

• Null findings: None located. No study with phosphate measured against a renal-function-matched comparison was found.
• At-risk subgroups: People with renal impairment (label).

Regulatory status

Both labels: "higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia and acidosis" in the antianabolic action warning, and if renal impairment exists even usual doses may lead to excessive systemic accumulation [1][2][3].

Population evidence

No human measurement of phosphate was retrieved. A 1967 rat study in Proc Soc Exp Biol Med (volume 125; title not captured in the excerpt read) gave tetracycline 400 mg/kg and reported arterial pH often below 7.10, marked hyperkalemia within 4 to 8 hours and azotemia, and cited human patients with impaired renal function and blood levels up to about 30 micrograms/mL who developed acidosis, hyperphosphatemia and azotemia [28]. That human context is a secondary citation inside an animal paper. Shils 1963 (Ann Intern Med 58:389-408) is a review on renal disease and tetracycline metabolic effects; only its opening paragraph was retrievable [26].

Mechanism

Present as pharmacology plus pharmacokinetics: reduced renal clearance raises drug levels, and the antianabolic action increases protein catabolism, adding to urea and phosphate load (label wording; the mechanism was described by Shils as unknown in the paragraph read [26]).

Counter-evidence held on record

Counter-evidence and confounding Hyperphosphatemia and acidosis are expected in renal failure regardless of drug, so confounding by indication is presumed (Hard Rule 6) and no source read separates the drug effect. Framing caution Excess/retention risk, not a deficiency. No phosphate or bicarbonate supplementation is implied; the label's remedy is dose adjustment and monitoring.

Limits on what this shows

• Null findings: Not located. No nitrogen balance, plasma amino acid or albumin study with tetracycline was found.

Regulatory status

"The antianabolic action of the tetracyclines may cause an increase in BUN"; adverse reactions: an increase in BUN has been reported and is dose related [1][3].

Population evidence

Boston Collaborative Drug Surveillance Program report, "Tetracycline and Drug-Attributed Rises in Blood Urea Nitrogen" (JAMA 1972;220:377; OpenAlex record has no abstract) [27]. Jick's reply letter (JAMA 1972;222:488; OpenAlex partial reconstruction) describes the original cases as BUN rises the attending physician judged possibly related to any drug, with a mean rise of 28.3 mg/100 mL (range 6 to 77), many with nausea and vomiting, each prompting drug discontinuation; how many involved tetracycline was not in the text retrieved [27]. Shils 1963 opening paragraph: an azotemic effect of tetracyclines seen sporadically, animal studies linking it to raised blood urea or non-protein nitrogen, mechanism unknown, and group members shown to increase urinary nitrogen excretion [26].

Mechanism

Described, not demonstrated here: inhibition of protein synthesis shifting nitrogen toward urea (label term "antianabolic"). The antibacterial 30S ribosomal action is documented in the label microbiology section; whether it explains the human BUN rise was not shown in the sources read.

Counter-evidence held on record

Counter-evidence and confounding Dehydration, renal impairment, gastrointestinal bleeding and the underlying infection all raise BUN. Hard Rule 2: this is an outcome entry and carries no nutrient claim. Framing caution A kidney-function monitoring prompt, not a protein or amino acid deficiency. No protein supplementation is implied.

Limits on what this shows

• Null findings: No tetracycline measurement of vitamin K or vitamin K dependent factors was found. The microbiome studies [16][17][18] did not measure vitamin K production.

Regulatory status

"The tetracyclines have been shown to depress plasma prothrombin activity" under anticoagulant therapy [1][2][3]. Vitamin K is not mentioned.

Population evidence

None with vitamin K measured after tetracycline. A PubMed listing for tetracycline and vitamin K (87 results, first 10 seen) held no record of oral tetracycline with vitamin K or prothrombin measured; the nearest were reviews and a tigecycline study [33]. CLASS EXTRAPOLATION: Sun 2024 [30] (Med Sci Monit 30:e944778; abstract reconstructed by OpenAlex): retrospective single-center study, 220 included patients given tigecycline 50 mg or 100 mg every 12 h; coagulopathy incidence 23.91%, worse prothrombin time, APTT and fibrinogen at the higher dose, and clotting times shortened after vitamin K1 in 72 patients. Cohort test: tigecycline was the drug studied; tetracycline was NOT in the cohort, so this is Tier C context and supports no grade by itself.

Mechanism

Plausible, not demonstrated for tetracycline: gut bacteria contribute to vitamin K supply (mechanism class G). The label does not state a mechanism, and the tigecycline abstract does not either.

Counter-evidence held on record

Counter-evidence and confounding A prothrombin change is a laboratory outcome with competing explanations, including a direct pharmacodynamic interaction with the anticoagulant (Hard Rule 2). Framing caution A monitoring prompt for people on anticoagulants, not a vitamin K deficiency claim. No vitamin K supplementation is implied.

Limits on what this shows

• Null findings: No tetracycline B12 or folate status study was found.

Regulatory status

No B vitamin statement in either label or the Drugs.com copy [1][2][3].

Population evidence

A PubMed listing for tetracycline and riboflavin deficiency (7 results, all shown) [31]. Records opened by PubMed uid, both without abstracts: Starshov 1959 (Antibiotiki 4:81-84, Russian) titled as prevention of riboflavin deficiency arising during chlortetracycline therapy of patients with acute dysentery, MeSH Vitamin B Deficiency (etiology); Doiphode and Bamji 1970 (Int Z Vitaminforsch 40:58-63) titled "Effect of aureomycin on the nutritional status of the B-vitamins in humans", typed Clinical Trial, MeSH Riboflavin/urine, Thiamine/urine, Niacinamide/urine. Also listed and not opened: a rat chlortetracycline flavin study (Yagi 1968) and a 1969 dysbacteriosis record. CLASS EXTRAPOLATION cohort test: the drug in these titles is chlortetracycline; tetracycline was NOT in the cohort, so these are Tier C and capped at yellow. Whether any of them found a deficit could not be confirmed.

Mechanism

Plausible, not demonstrated: suppression of vitamin-synthesizing gut bacteria (mechanism class G). The microbiome studies [16][17] did not measure vitamin production.

Counter-evidence held on record

Counter-evidence and confounding Dysentery patients are malnourished and malabsorbing, so any riboflavin deficiency in them is confounded by indication (Hard Rule 6). The grade reflects a plausible class signal, not a confirmed one. Framing caution Not a B vitamin deficiency claim for tetracycline and no basis for B vitamin supplementation.