@article {Jaakkola:January 2006:0306-5251:70,
	author = "Jaakkola, Tiina",
	author = "Backman, Janne T.",
	author = "Neuvonen, Mikko",
	author = "Laitila, Jouko",
	author = "Neuvonen, Pertti J.",
	title = "Effect of rifampicin on the pharmacokinetics of pioglitazone",
	journal = "British Journal of Clinical Pharmacology",
	volume = "61",
	year = "January 2006",
	abstract = "Aims <P></P>The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans. Methods <P></P>In a randomized, two-phase crossover study, ten&#8201;healthy subjects ingested either 600&#8201;mg rifampicin or placebo once daily for 6&#8201;days. On the last day, they received a single oral dose of 30&#8201;mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M-IV and M-III into urine were measured up to 48&#8201;h. Results <P></P>Rifampicin decreased the mean total area under the plasma concentration-time curve (AUC<SUB>0&#8722;&#8734;</SUB>) of pioglitazone by 54% (range 20&#8211;66%; <I>P</I>&#8201;&#61;&#8201;0.0007; 95% confidence interval &#8722;78 to &#8722;30%) and shortened its dominant elimination half-life (<I>t</I><SUB>1&#47;2</SUB>) from 4.9 to 2.3&#8201;h (<I>P</I>&#8201;&#61;&#8201;0.0002). No significant effect on peak concentration (<I>C</I><SUB><I>max</I></SUB>) or time to peak (<I>t</I><SUB><I>max</I></SUB>) was observed. Rifampicin increased the apparent formation rate of M-IV and shortened its <I>t</I><SUB><I>max</I></SUB> (<I>P</I>&#8201;&#60;&#8201;0.01). It also decreased the AUC<SUB>0&#8722;&#8734;</SUB> of M-IV (by 34%; <I>P</I>&#8201;&#61;&#8201;0.0055) and M-III (by 39%; <I>P</I>&#8201;&#61;&#8201;0.0026), shortened their <I>t</I>1&#47;2 (M-IV by 50%; <I>P</I>&#8201;&#61;&#8201;0.0008, and M-III by 55%; <I>P</I>&#8201;&#61;&#8201;0.0016) and increased the AUC<SUB>0&#8722;&#8734;</SUB> ratios of M-IV and M-III to pioglitazone by 44% (<I>P</I>&#8201;&#61;&#8201;0.0011) and 32% (<I>P</I>&#8201;&#61;&#8201;0.0027), respectively. Rifampicin increased the M-IV&#47;pioglitazone and M-III&#47;pioglitazone ratios in urine by 98% (<I>P</I>&#8201;&#61;&#8201;0.0015) and 95% (<I>P</I>&#8201;&#61;&#8201;0.0024). A previously unrecognized metabolite M-XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M-XI to pioglitazone by 240% (<I>P</I>&#8201;&#61;&#8201;0.0020). Conclusions <P></P>Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.",
	pages = "70-78(9)",
	url = "http://www.ingentaconnect.com/content/bsc/bjcp/2006/00000061/00000001/art00009"
	doi = "doi:10.1111/j.1365-2125.2005.02515.x"
}