Is there a risk for interaction between colchicine and the following drugs: simvastatin, glibenclam

Fråga: Is there a risk for interaction between colchicine and the following drugs: simvastatin, glibenclamide, omeprazole (Losec), levonorgestrel + ethinylestradiol (Neovletta), loratadine (Clarityn), budesonide (Pulmicort), terbutaline (Bricanyl), salmeterol (Serevent), antifoam (Dimetikon)? Would lansoprazole (Lanzo) be a better alternative to omeprazole?

A woman born in 1955 is on treatment with these drugs and should need addition of colchicine.

Sammanfattning: There is a risk of interaction between colchicine and simvastatin. Both drugs may induce myopathy. Simvastatin may inhibit the metabolism of colchicine to some extent resulting in higher plasma levels of colchicine. Simultaneous use of these two drugs should be avoided. In general all statins should be avoided in combination with colchicine since they are all potentially myotoxic. Furthermore colchicine decreases the release of insulin and may impair the metabolic control with glibenclamide. Lansoprazol offers no advantage to omeprazol pharmacokinetically.

Svar: Colchicine is metabolised mainly in the liver and is partly deacetylated to R-NH2 deacetyl-colchicine and partly demethylated to demethylcolchicine, which is glucuronidated (1). After enterohepatic recirculation the major part is excreted in the feces as inactive metabolites. 10-20 % can be excreted unchanged via the kidneys. The demethylation is mediated mainly through the cytochrome P450 system isoenzyme CYP3A4. Simvastatin is also metabolised by CYP3A4 (2).

There is a case report of a patient with chronic renal insufficiency treated with simvastatin for two years without side effects (3). He had recurrent acute goiter and treatment with colchicine 0.5 mg x 2 was started. After two weeks the patient had difficulty climb the stairs. One week later he could only walk on level surface with assistance. He did not have myalgia. Physical examination revealed marked symmetric proximal weakness worse in the lower limbs. CK was increased fourfold and EMG was pathologic. Both drugs were discontinued. After one week the patient could walk slowly and two weeks later he could ascend stairs unaided. CK levels normalized in two weeks. Both colchicine and simvastatin can cause myopathy. It has been clinically observed that colchicine induced myopathy presents as subacute proximal weakness without muscle pain whereas myopathy induced by HMG-CoA reductase-inhibitors is painful. It was assumed that simvastatin had inhibited the metabolism of colchicine in this case and it was concluded that combination of these two drugs is not advisable, since both can cause myopathy and are metabolised by the same enzyme system.

If treatment with HMG-CoA reductase-inhibitors is necessary during treatment with colchicine, pravastatin is a better alternative since this drug is not significantly metabolised by the CYP system (2). However, pravastatin is myotoxic although possibly less than the other statins due its relatively poor uptake by the myocytes (4).

There is a report of a group of patients experiencing diarrhea during treatment with colchicine (1). Their serum cholesterol levels decreased concomitantly with an increase of sterols and bile acids in feces. Thus there may be less need for HMG-CoA reductase-inhibitors during treatment with colchicine.

Glibenclamide is metabolised via hydroxylation. In studies using pooled human liver microsomes glibenclamide showed potent inhibition of CYP2C9 and weak inhibition of CYP3A4 (5). Theoretically there is a possibility of interaction between colchicine and glibenclamide by competitive inhibition of CYP3A4. However, no reports of such an interaction have been found in the literature. More important is probably the observation that colchicine decreases the release of insulin after glucose administration (6).

Omeprazole is metabolised mainly by CYP2C19 and only to less extent by CYP3A4 (7). Lansoprazole appears to be mainly metabolised by CYP3A4 and is an inducer of this enzyme in studies using hepatocytes (7). It is, however, unlikely that omeprazol or lansoprazol will cause clinically significant drug interactions considering the doses used (7). Pharmacokinetically lansoprazol offers no advantage to omeprazole.

Oral contraceptive agents are metabolised by cytochrome P450 isoenzyme CYP3A4 and through glucuronidation (8). Theoretically there may be an interaction between them and colchicine by competitive inhibition of CYP3A4. However, most pharmacokinetic interactions with oral contraceptives reported are induction rather than inhibition. No reports of interactions between colchicine and oral contraceptives have been found in the literature.

Loratadine is preferentially metabolised by the cytochrome P450 isoenzyme CYP3A4 to its active metabolite but can also be metabolised by CYP2D6 in the presence of inhibitors of CYP3A4 (9). Theoretically colchicine and loratadine could interact by competitive inhibition of CYP3A4. However there are no reports in the literature of clinically observed interactions

Concerning budesonide, terbutaline and salmeterol: no clinically relevant interactions have been found reported between antiasthma drugs and colchicine.

Antifoam is not absorbed and there should be no risk of interaction.

Clinically important drug interactions with colchicine resulting in toxicity can be expected and have also been reported with drugs that are strong inhibitors of CYP3A4, for example erythromycin (10, 11). Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p. C320-22. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur J Clin Pharmacol 2001;57:357-64. Hsu WC, Chen WH, Chang MT, Chiu HC. Colchicine-induced acute myopathy in a patient with concomitant use of simvastatin. Clin Neuropharmacol 2002;25(5):266-8. Drugline no 18935 (year 2002) Kim KA, Park JY. Short communication. Inhibitory effect of glyburide on human cytochrome P450 isoforms in human liver microsomes. Drug Metab Dispos 2003;31:1090-2. Hardman JG, Limibrd LE, Goodman Gilman A, editors. Goodman & Gilman´s The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 720 Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999. p. O17 Drugline no 19823 (year 2003) Loratadine. Drugdex(R) System; Micromedex, Inc., Englewood, Colorado (Edition expires 3/2004) Tateishi T, Soucek P, Caraco Y, Guengerich FP, Wood AJ. Colchicine biotransformation by human liver microsomes. Identification of CYP3A4 as the major isoform responsible for colchicine demethylation. Biochem Pharmacol 1997;53(1):111-6. Stockley IH. Drug interactions. 6th ed. London: The Pharmaceutical Press; 2002. p.