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Drug Interactions between clarithromycin and quinine

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

clarithromycin quiNINE

Applies to: clarithromycin and quinine

GENERALLY AVOID: Coadministration with ketolide and macrolide antibiotics that inhibit CYP450 3A4 may significantly increase the plasma concentrations of quinine, which is primarily metabolized by the isoenzyme. In ten healthy volunteers, administration of a single 600 mg oral dose of quinine sulfate in combination with the potent CYP450 3A4 inhibitor troleandomycin (500 mg orally every 8 hours for 48 hours) significantly increased the mean quinine peak plasma concentration (Cmax), systemic exposure (AUC) and terminal elimination half-life by 26%, 90% and 63%, respectively, and decreased the mean oral clearance (Cl/F) by 45% compared to administration of quinine alone. Troleandomycin also reduced the average Cmax, AUC and apparent formation clearance of the main metabolite, 3-hydroxyquinine, by 75%, 58% and 81%, respectively. Other ketolides and macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and telithromycin. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4. Clinically, high plasma levels of quinine may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. In addition, clarithromycin, erythromycin, and telithromycin have all been individually associated with QT interval prolongation, thus additive effects may occur during concomitant use with quinine. Fatal torsade de pointes arrhythmia was reported in an elderly patient who received quinine in combination with erythromycin and dopamine. However, a causal relationship was not established in this case.

MANAGEMENT: The use of quinine in combination with ketolide and macrolide antibiotics that inhibit CYP450 3A4 should generally be avoided. Azithromycin may be a safer alternative during therapy with quinine.

References

  1. Zhao XJ, Ishizaki T (1997) "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, 44, p. 505-11
  2. Mirghani RA, Hellgren U, Westerberg PA, Ericsson O, Bertilsson L, Gustafsson LL (1999) "The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo." Clin Pharmacol Ther, 66, p. 454-60
  3. Zhao XJ, Ishizaki T (1999) "A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (K-i) and type of inhibition." Eur J Drug Metab Pharm, 24, p. 272-8
  4. Wanwimolruk S, Paine MF, Pusek SN, Watkins PB (2002) "Is quinine a suitable probe to assess the hepatic drug-metabolizing enzyme CYP3A4?" Br J Clin Pharmacol, 54, p. 643-51
  5. Mirghani RA, Ericsson O, Tybring G, Gustafsson LL, Bertilsson L (2003) "Quinine 3-hydroxylation as a biomarker reaction for the activity of CYP3A4 in man." Eur J Clin Pharmacol, 59, p. 23-8
  6. Mirghani RA, Hellgren U, Bertilsson L, Gustafsson LL, Ericsson O (2003) "Metabolism and elimination of quinine in healthy volunteers." Eur J Clin Pharmacol
  7. (2006) "Product Information. Qualaquin (quinine)." AR Scientific Inc
  8. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S (1997) "Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine." Br J Clin Pharmacol, 43, p. 245-52
  9. Mirghani RA, Yasar U, Zheng T, et al. (2002) "Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway." Drug Metab Dispos, 30, p. 1368-71
View all 9 references

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Drug and food interactions

Minor

clarithromycin food

Applies to: clarithromycin

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.

References

  1. Cheng KL, Nafziger AN, Peloquin CA, Amsden GW (1998) "Effect of grapefruit juice on clarithromycin pharmacokinetics." Antimicrob Agents Chemother, 42, p. 927-9

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Minor

quiNINE food

Applies to: quinine

Coadministration with grapefruit juice does not appear to affect the pharmacokinetics of quinine in a clinically relevant manner. Although grapefruit juice is an inhibitor of CYP450 3A4 and quinine is metabolized by this pathway to its major metabolite, 3-hydroxyquinine, a study of ten healthy volunteers found no significant differences in quinine peak plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life, systemic exposure (AUC), or apparent oral clearance (Cl/F) when a single 600 mg oral dose of quinine sulfate was administered in combination with 200 mL of orange juice (control), half-strength grapefruit juice, and full-strength grapefruit juice twice daily for 6 days each, separated by a 2-week washout period. Relative to the control period, the apparent renal clearance of quinine was markedly increased by 81% during treatment with half-strength grapefruit juice. However, since renal clearance accounts for approximately 6% of the total clearance of quinine, this change would likely have minimal clinical impact. The lack of a significant interaction is probably due to the fact that grapefruit juice primarily inhibits intestinal rather than hepatic CYP450 3A4, and quinine is not known to undergo significant presystemic metabolism as evidenced by its relatively high oral bioavailability (76% to 88%). Nevertheless, excessive consumption of grapefruit juice and tonic water (which contains quinine) was suspected as the cause of torsade de pointes arrhythmia in a patient with a history of asymptomatic long QT syndrome. Treatment with magnesium sulfate and metoprolol had no effect, but the arrhythmia resolved spontaneously 48 hours after discontinuation of the drinks. Based on current data, moderate grapefruit juice consumption is probably safe for the majority of patients taking quinine.

References

  1. Ho PC, Chalcroft SC, Coville PF, Wanwimolruk S (1999) "Grapefruit juice has no effect on quinine pharmacokinetics." Eur J Clin Pharmacol, 55, p. 393-8
  2. Hermans K, Stockman D, Van den Branden F (2003) "Grapefruit and tonic: a deadly combination in a patient with the long QT syndrome." Am J Med, 114, p. 511-2
  3. (2006) "Product Information. Qualaquin (quinine)." AR Scientific Inc
  4. Zhang H, Coville PF, Walker RJ, Miners JO, Birkett DJ, Wanwimolruk S (1997) "Evidence for involvement of human CYP3A in the 3-hydroxylation of quinine." Br J Clin Pharmacol, 43, p. 245-52
  5. Mirghani RA, Yasar U, Zheng T, et al. (2002) "Enzyme kinetics for the formation of 3-hydroxyquinine and three new metabolites of quinine in vitro; 3-hydroxylation by CYP3A4 is indeed the major metabolic pathway." Drug Metab Dispos, 30, p. 1368-71
View all 5 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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