Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 58-year-old woman who had been taking digoxin 0.25 mg/day for more than 35 years for heart palpitations after mitral valve repair was prescribed a 5-day course of telithromycin for acute bronchitis. On the sixth day of therapy, she came to the emergency department complaining of general malaise and having experienced three episodes of syncope over the previous 2 days. Laboratory analysis revealed elevated digoxin plasma levels, and electrocardiography showed several nonspecific repolarization anomalies. Telithromycin is known to increase digoxin plasma levels; however, the clinical significance of this interaction is not known. To our knowledge, this is the first report of elevated plasma digoxin levels associated with signs and symptoms of toxicity. This drug interaction-determined as probable according to the Naranjo adverse drug reaction probability scale-may be mediated by P-glycoprotein. By inhibiting the transport of digoxin by P-glycoprotein, telithromycin may have decreased digoxin elimination in the intestinal lumen and its renal tubular excretion, resulting in elevated plasma levels and drug toxicity. Clinicians should be aware of possible digoxin toxicity after concomitant administration with telithromycin, especially in patients who are at risk, such as those with electrolyte abnormalities and decreased renal function.
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PMID:Telithromycin-induced digoxin toxicity and electrocardiographic changes. 1671 40

Levofloxacin (LEV) is a broad-spectrum fluoroquinolone used to treat pneumonia, urinary tract infections, chronic bacterial bronchitis, and prostatitis. Efflux transporters, primarily P-glycoprotein (P-gp), are involved in LEV's tissue penetration. In the present work, LEV free lung and prostate interstitial space fluid (ISF) concentrations were evaluated by microdialysis in Wistar rats after intravenous (i.v.) and intratracheal (i.t.) administration (7 mg/kg of body weight) with and without coadministration of the P-gp inhibitor tariquidar (TAR; 15 mg/kg administered i.v.). Plasma and tissue concentration/time profiles were evaluated by noncompartmental analysis (NCA) and population pharmacokinetics (popPK) analysis. The NCA showed significant differences in bioavailability (F) for the control group (0.4) and the TAR group (0.86) after i.t. administration. A four-compartment model simultaneously characterized total plasma and free lung (compartment 2) and prostate (compartment 3) ISF concentrations. Statistically significant differences in lung and prostate average ISF concentrations and levels of kidney active secretion in the TAR group from those measured for the control group (LEV alone) were observed. The estimated population means were as follows: volume of the central compartment (V1), 0.321 liters; total plasma clearance (CL), 0.220 liters/h; TAR plasma clearance (CLTAR), 0.180 liters/h. The intercompartmental distribution rate constants (K values) were as follows: K12, 8.826 h(-1); K21, 7.271 h(-1); K13, 0.047 h(-1); K31, 7.738 h(-1); K14, 0.908 h(-1); K41, 0.409 h(-1); K21 lung TAR (K21LTAR), 8.883 h(-1); K31 prostate TAR (K31PTAR), 4.377 h(-1). The presence of P-gp considerably impacted the active renal secretion of LEV but had only a minor impact on the efflux from the lung following intratracheal dosing. Our results strongly support the idea of a role of efflux transporters other than P-gp contributing to LEV's tissue penetration into the prostrate.
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PMID:Simultaneous Semimechanistic Population Analyses of Levofloxacin in Plasma, Lung, and Prostate To Describe the Influence of Efflux Transporters on Drug Distribution following Intravenous and Intratracheal Administration. 2662 23