Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine.
OBJECTIVE
Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism.


METHODS
In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases.


RESULTS
Rifampicin moderately reduced the peak plasma concentration (by 51%; P = 0.002) and area under the plasma concentration-time curve [AUC(0-infinity)] (by 54%; P = 0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0-infinity) ratios were slightly (by 30%; P = 0.014; and by 38%; P = 0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P < 0.005), but that of M-10 was increased (P = 0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P = 0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P = 0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0-infinity) of tizanidine and the tizanidine/M-3 AUC(0-infinity) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin.


CONCLUSIONS
Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type.
Backman
Janne T
JT
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. janne.backman@hus.fi
Granfors
Marika T
MT
Neuvonen
Pertti J
PJ
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002110:Caffeine / Q000493:pharmacokinetics*; D003000:Clonidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism*; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002110:Caffeine; C023754:tizanidine; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D003000:Clonidine; D012293:Rifampin