Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects

Ebert, Ulrike; Thong, Nancy; Oertel, Reinhard; Kirch, Wilhelm

doi:10.1007/s002280000146

Cited by 66 publications

(36 citation statements)

References 19 publications

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“…RIF significantly decreased lamotrigine exposure in a blinded study in 10 healthy volunteers, probably due to an induction of the UGT enzyme system [120]. …”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.

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“…RIF significantly decreased lamotrigine exposure in a blinded study in 10 healthy volunteers, probably due to an induction of the UGT enzyme system [120]. …”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

et al. 2011

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“…Rifampin is a common interacting drug involved in glucuronidation-mediated DDI (13)(14)(15)(16)(17)(18). In our study, the C max and AUC of morinidazole in healthy subjects were decreased significantly, by around 20% to 30%, after pretreatment with rifampin, while only the C max of M8-1was increased 1.3-fold, without a change of AUC.…”

Section: Discussionmentioning

confidence: 99%

Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

Pang

Zhang

Gao

et al. 2014

Antimicrob Agents Chemother

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Morinidazole, a 5-nitroimidazole antimicrobial drug, has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. It was reported that drug-drug interaction happened after the coadministration of ornidazole, an analog of morinidazole, and rifampin or ketoconazole. Therefore, we measured the plasma pharmacokinetics (PK) of morinidazole and its metabolites in the healthy Chinese volunteers prior to and following the administration of rifampin or ketoconazole using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the concentration-time curve from time 0 to time t (AUC 0-t ) and maximum concentration in serum (C max ) of morinidazole were decreased by 28% and 23%, respectively, after 6 days of exposure to 600 mg of rifampin once daily; the C max s of N ؉ -glucuronides were increased by 14%, while their AUC 0-t s were hardly changed. After 7 days of exposure to 200 mg of ketoconazole once daily, the AUC 0-t and C max of the parent drug were not affected significantly. C max s of N ؉ -glucuronides were decreased by 23%; AUC 0-t s were decreased by 14%. The exposure of sulfate conjugate was hardly changed after the coadministration of rifampin or ketoconazole. Using recombinant enzyme of UGT1A9 and human hepatocytes, the mechanism of the altered PK behaviors of morinidazole and its metabolites was investigated. In human hepatocytes, ketoconazole dose dependently inhibited the formation of N ؉ -glucuronides (50% inhibitory concentration [IC 50 ], 1.5 M), while rifampin induced the mRNA level of UGT1A9 by 28% and the activity of UGT1A9 by 53%. In conclusion, the effects of rifampin and ketoconazole on the plasma exposures of morinidazole and N ؉ -glucuronide are less than 50%; therefore, rifampin and ketoconazole have little clinical significance in the pharmacokinetics of morinidazole. Morinidazole is developed as a 5-nitroimidazole antimicrobial injection with potent activities against anaerobic Gram-negative sporeless bacilli and Gram-positive cocci (1). Its efficacy against Clostridium perfringens, Bacteroides fragilis, Veillonella parvula, Bacteroides distasonis, Bacteroides ovatus, Bacteroides vulgatus, and Bacteroides melaninogenicus is equal to that of ornidazole and superior to those of metronidazole and tinidazole. It has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. However, its antibacterial spectrum is still limited; thus, there is the possibility of concomitant administration with other antibacterial agents in the treatment of mixed infections. It was reported that drug-drug interaction (DDI) happened after the coadministration of ornidazole, an analog of morinidazole, with rifampin or ketoconazole. The pharmacokinetic parameters of ornidazole in healthy volunteers-area under the curve (AUC), peak concentration (C max ), elimination half-life (t 1/2 ), and clearance (CL)-were decreased by 21.16%, 20.43%, 18.11%, and 32.14%, respectively, by rifampin. The altered pharmacok...

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“…The serum concentrations of lamotrigine should therefore be closely monitored, and this interaction is of major importance, as lamotrigine is often a preferred choice of drug in female patients (Level 1 interaction, according to [76]). Rifampicin has been shown to increase lamotrigine clearance of about 50 % [103]. …”

Section: Interactions Between Aeds and Other Drugsmentioning

confidence: 99%

Antiepileptic Drug Interactions - Principles and Clinical Implications

Johannessen

Landmark²

2010

286

212

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Antiepileptic drugs (AEDs) are widely used as long-term adjunctive therapy or as monotherapy in epilepsy and other indications and consist of a group of drugs that are highly susceptible to drug interactions. The purpose of the present review is to focus upon clinically relevant interactions where AEDs are involved and especially on pharmacokinetic interactions. The older AEDs are susceptible to cause induction (carbamazepine, phenobarbital, phenytoin, primidone) or inhibition (valproic acid), resulting in a decrease or increase, respectively, in the serum concentration of other AEDs, as well as other drug classes (anticoagulants, oral contraceptives, antidepressants, antipsychotics, antimicrobal drugs, antineoplastic drugs, and immunosupressants). Conversely, the serum concentrations of AEDs may be increased by enzyme inhibitors among antidepressants and antipsychotics, antimicrobal drugs (as macrolides or isoniazid) and decreased by other mechanisms as induction, reduced absorption or excretion (as oral contraceptives, cimetidine, probenicid and antacides). Pharmacokinetic interactions involving newer AEDs include the enzyme inhibitors felbamate, rufinamide, and stiripentol and the inducers oxcarbazepine and topiramate. Lamotrigine is affected by these drugs, older AEDs and other drug classes as oral contraceptives. Individual AED interactions may be divided into three levels depending on the clinical consequences of alterations in serum concentrations. This approach may point to interactions of specific importance, although it should be implemented with caution, as it is not meant to oversimplify fact matters. Level 1 involves serious clinical consequences, and the combination should be avoided. Level 2 usually implies cautiousness and possible dosage adjustments, as the combination may not be possible to avoid. Level 3 refers to interactions where dosage adjustments are usually not necessary. Updated knowledge regarding drug interactions is important to predict the potential for harmful or lacking effects involving AEDs.

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Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects

Cited by 66 publications

References 19 publications

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

Pharmacokinetic Drug Interactions of Antimicrobial Drugs: A Systematic Review on Oxazolidinones, Rifamycines, Macrolides, Fluoroquinolones, and Beta-Lactams

Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects

Antiepileptic Drug Interactions - Principles and Clinical Implications

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