Acute Porphyria Drugs

Acute Porphyria Drug Database

J01AA02 - Doxycycline
Propably not porphyrinogenic
PNP
Rationale
Doxycycline is not listed as an inducer or as a mechanism–based inhibitor of any CYP enzymes. It is mainly excreted unchanged in urine and faeces. CYP enzymes are most probably only involved in the metabolism to a minor extent. Side effects such as nausea, vomiting and diarrhoea may be potentially porphyrinogenic through reduction in carbohydrate intake.
Chemical description
Doxycycline is a tetracycline broadspectrum antibiotic with alkylamino group. It is 3-5 times more lipophilic than tetracycline (Agwuh 2006, Whelton 1974).
Therapeutic characteristics
It is used in the treatment of infections caused by tetracycline sensitive aerobe and anaerobe Gram-positive and Gram-negative microorganisms. Nausea, vomiting and diarrhoea are reported as very common side effects.
Hepatic exposure
Significant.
Metabolism and pharmakokinetics
In vitro studies suggests that doxycycline might be a substrate or an inhibitor of CYP3A4 (Eisen 2010, Zhao 1997, 1999) but no data indicates mechanism-based inhibition. It is highly protein bound (90%) and diffuses from blood into the intestinal lumen, where cationic chelation occurs. This prevents reabsorption (Whelton 1974) and it is then excreted in faeces. The remainder (30-60%) of administered doxycycline is normally excreted unchanged in urine (Agwuh 2006, Houin 1983, SPC). Half-life elimination: single dose 16-18 hours, following multiple doses: 22 hours. In vivo studies have shown that the half-life of doxycycline shortens when administered with phenobarbital, an inducer of CYP enzymes (Nuevonen 1974). Rifampicin, an inducer of CYP enzymes as well (Kolars 1992) has also been shown to lower the levels of doxycycline in plasma when co-administered (Colmenero 1994). These data indicates that doxycycline might be a substrate of CYP enzymes and that CYP enzymes may be involved in its metabolism to some extent. There are no reports of doxycycline as a perpetrator in drug-drug-interactions concerning CYP enzymes.
Personal communication
S. Thunell: 2 reports of safe use.
Published experience
One report of uneventful use of doxycycline in female AIP patient (7 days). Urinary porphyrin concentrations was measured before and after treatment, and doxycycline was considered entirely safe (Smith JR 1989).
IPNet drug reports
Uneventful use reported in 9 patients with acute porphyria.

References

  1. Scientific articles
  2. Colmenero JD, Fernández-Gallardo LC Possible Implications of Doxycycline-Rifampin interaction for Treatment of Brucellosis. Antimicrobial Agents Chemotherapy. 1994 Dec;38(12):2798-802. PMID 7695265. #4489
  3. Agwuh K. N. and MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. Journal of Antimicrobial Chemotherapy. 2006;58:256â-265. PMID 16816396. #1602
  4. Eisen DP. Doxycycline. Kucers’ the Use of Antibiotics 6th Edition, by Grayson L. M, Kucers A. et al. 2010. 851-871. #1604
  5. Houin G, Brunner F. The effects of chronic renal insufficiency on the pharmacokinetics of doxycycline in man. Br. J. clin. Pharmac. 1983;16:245-252. #1605
  6. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest. 1992 Nov;90(5):1871-8. PMID 1430211. #4490
  7. Neuvonen PJ and Penttilä O. Interaction between Doxycycline and Barbiturates. British Medical Journal. 1974;1:535-536. PMID 4817187. #4491
  8. Smith JR and Forster SM. Chlamydial infection: which antibiotic for patients with acute intermittent porphyria? Genitourin Med. 1989 Jun;65(3):199-200. PMID 2759614. #4492
  9. Whelton A. Doxycycline pharmacokinetics in the absence of renal function. Kidney international. 1974;5:365-371. PMID 4427416. #4493
  10. Zhao XJ and Ishizaki T. A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition. Eur J Drug Metab Pharmacokinet. 1999 Jul-Sep; 24(3):272-8. PMID 10716067. #4495
  11. Zhao XJ and Ishizaki T. Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes. Br J Clin Pharmacol. 1997 Nov; 44(5):505-11. PMID 9384469. #4494
  12. Drug reference publications
  13. Up to date. Doxycycline. #1610
  14. Summary of Product Characteristics
  15. Norwegian medicines agency. Summary of Product Characteristics (SPC). Doksysyklin. #1607
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