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Category: Bacterial Pathogenesis
Drug Interactions during Anti-Infective Treatments, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap54-1.gif /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap54-2.gifAbstract:
The chapter presents an overview of drug-drug interactions that occur during anti-infective treatments. The solubilization of antifungal azoles, indinavir, delavirdine, or even dapsone requires an acidic pH, so acid suppressants greatly reduce their bioavailability. Di- or trivalent cations lead to the formation of insoluble or weakly soluble chelates with FQ, tetracyclines, rifampin, and ethambutol. Any metabolizable drug that penetrates the enterocyte and gains access to its cytosol will be metabolized by enterocytic CYP, a new stage which may be the subject of an interaction either by competition between substrates or by modification of the metabolic capacities of the enterocyte following coprescription of an enzyme inducer or inhibitor. Pulmonary CYPs are induced by cigarette smoke, a means of eliminating more actively chemicals contained in the smoke. Nowadays, evaluation of potential drug-drug interactions is mandatory for the registration of new drugs by regulatory agencies. The participation of substrate metabolites in drug-drug interactions at both levels, drug transport proteins and CYP enzymes, could also lead to discrepancies. In the vast literature dedicated to metabolic drug interactions, CYP3A4 has received the greatest attention. In the vast literature dedicated to metabolic drug interactions, CYP3A4 has received the greatest attention. The question of a fixed margin versus a varying margin in noninferiority trials has been addressed statistically for anti-infective treatments, taking into account the variable underlying clinical success rate of the reference treatment.
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Epithelial cell transporters and their main substrates, inhibitors, and inducers. *, substrates = conjugated (e.g., BSP conjugates) and unconjugated anions; cMOAT is MRP2.
Metabolism rate of four substrates of CYP3A4 by rat intestinal or hepatic microsomal preparations (from Aiba et al., 2003 )
Postulated changes in substrate metabolism as a function of enzyme and transporter inhibition and induction (adapted from Benet et al., 2003 )
Theoretical pharmacokinetic modifications in an induction or inhibition process
Illustration of the digoxin-drug interaction case
Extent of decrease in fluoroquinolone Cmax and AUC when coprescribed with a gastroprotective drug a
Behavior of antiproteases vis-à-vis CYP3A4 and P-gp
Distribution of substrates, enzyme inducers, and enzyme inhibitors according to the different CYPs
Substrates for CYP isoforms
Hepatic and intestinal distributions of the isoforms CYP3A4, -2D6, and -3A9 in the rat a
Inhibition of the metabolism of theophylline
Multiplication factor of the half-life of theophylline in combination with an FQ
Drug interaction involving macrolides and ketolides
Decrease in CYP activity according to Child-Pugh score
Decrease in CYP activity according to the presence or absence of cholestasis
Relative levels of P-gp in CNS and GI tract on Western immunoblot of FVB mouse from days 0 to 21 of life
CYP enzyme activity in infants (1 to 28 days) as a fraction of adult activity
Urinary excretion of glucuronidation and sulfatation activities for paracetamol
Antipyrine half-life in different populations
Influence of environmental chemicals, social drugs, and life habits on epithelial cell transporter capacity and CYP enzyme activity
Substrates usually used as specific CYP probes
Suggested gender differences in selected drug transporters and metabolizing enzymes
AUC increases over baseline of 13 different drugs when administered with grapefruit juice
Mean urinary recovery of pefloxacin and main metabolites after oral administration of a single dose of pefloxacin a
Species-dependent toxic effects of chemicals
Species defects in common metabolic reactions