![]() Given the complex time course of enzyme/transporter induction by rifampicin, potential drug–drug interactions should be considered when starting or discontinuing treatment with rifampicin. Overall, the effects of rifampicin on drug metabolism and transport are broad and have an established clinical significance. Due to these properties, rifampicin exhibits substantial effects on the pharmacokinetics of drugs that undergo extensive CYP-mediated oxidative metabolism and/or are subject to P-glycoprotein-mediated transport. The mechanism of rifampicin-mediated induction of enzymes and membrane transporters is primarily through the binding to the nuclear pregnane X receptor among other nuclear receptors. P-glycoprotein and ABCB1) as well as the glucuronidation of certain drugs, such as S-oxazepam and rofecoxib. Furthermore, in humans rifampicin can induce the expression of some efflux transporters (e.g. It has its greatest effects on the expression of CYP3A4 in both the intestinal wall and the liver. Rifampicin is a potent inducer of several CYP isoforms, including CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, and is a weak inducer of CYP1A2. Rifampicin is an antibiotic used frequently for the treatment of pulmonary tuberculosis. ![]() Collectively, it appears that the disposition of roflumilast and roflumilast N-oxide is susceptible to alteration by induction or inhibition of several metabolizing enzymes. In a study with fluvoxamine (which is a more specific CYP1A2 inhibitor and an in vivo inhibitor of CYP2C19, 40-fold more potent than in vitro), a 2.5-fold increase in the AUC of the parent compound and only 50% increase of the metabolite were observed. Results of drug–drug interaction studies with CYP3A4 inhibitors ketoconazole and erythromycin showed that the AUC of the parent compound roflumilast changed almost twofold, whereas the AUC of the metabolite roflumilast N-oxide remained relatively unchanged. From previous studies, it is known that only very small amounts (<1%) of roflumilast and roflumilast N-oxide are excreted unchanged via the renal route. In vitro data suggest that roflumilast N-oxide is metabolized by CYP3A4 with a contribution from CYP2C19 and extrahepatic CYP1A1. After intake of roflumilast, the mean peak plasma concentration ( C max) of roflumilast is reached in <1 h the C max of roflumilast N-oxide is reached in about 4 h. Roflumilast N-oxide is the major contributor to the overall PDE4 inhibitory activity of roflumilast. Roflumilast and roflumilast N-oxide follow linear pharmacokinetics and show a predictable and dose-proportional, intraindividual pharmacokinetics under steady-state conditions. area under the plasma concentration curve (AUC) exceeds that of the parent drug by about 10-fold. ![]() The t 1/2 of roflumilast N-oxide is about 27 h and its total exposure, i.e. In humans, the major step in the metabolism of roflumilast is N-oxidation by cytochrome P450 (CYP) isozymes 3A4 and CYP1A2 to the pharmacologically active metabolite roflumilast N-oxide, which in vivo has a similar phosphodiesterase selectivity profile and intrinsic PDE4 inhibitory activity as the parent drug roflumilast. The mean absolute bioavailability of a 500-µg immediate-release tablet is 79% and the apparent terminal plasma disposition half-life ( t 1/2) is about 17 h. Roflumilast is rapidly absorbed after oral administration. In clinical studies, an oral, once-daily dose of roflumilast 500 µg was shown to improve lung function, reduce exacerbations, and to be safe in patients with COPD. Roflumilast exerts its anti-inflammatory properties by amplifying intracellular cAMP signalling, which attenuates the inflammatory response mediated by various immune-modulatory cells. Roflumilast is a targeted inhibitor of PDE4. PDE4 catalyses the hydrolysis of intracellular cAMP, an important second messenger for the function of inflammatory and airway smooth muscle cells. The cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase 4 (PDE4) represents a novel target for the treatment of chronic inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD).
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