Drug Interactions during Anti-Infective Treatments

O. Petitjean; P. Nicolas; M. Tod; C. Padoin; A. Jacolot

doi:10.1128/9781555815929.ch54

Chapter 54 : Drug Interactions during Anti-Infective Treatments

Authors: O. Petitjean, P. Nicolas, M. Tod, C. Padoin, A. Jacolot

Content Type: Reference

Publication Year: 2005

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555815929

Chapter DOI: 10.1128/9781555815929.ch54

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Abstract:

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.

Citation: Petitjean O, Nicolas P, Tod M, Padoin C, Jacolot A. 2005. Drug Interactions during Anti-Infective Treatments, p 1320-1352. In Bryskier, M.D. A (ed), Antimicrobial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555815929.ch54

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Drug Interactions during Anti-Infective Treatments

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Figure 1

Epithelial cell transporters and their main substrates, inhibitors, and inducers. *, substrates = conjugated (e.g., BSP conjugates) and unconjugated anions; cMOAT is MRP2.

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Figure 1

Epithelial cell transporters and their main substrates, inhibitors, and inducers. *, substrates = conjugated (e.g., BSP conjugates) and unconjugated anions; cMOAT is MRP2.

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Figure 2

Metabolism rate of four substrates of CYP3A4 by rat intestinal or hepatic microsomal preparations (from Aiba et al., 2003 )

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Figure 2

Metabolism rate of four substrates of CYP3A4 by rat intestinal or hepatic microsomal preparations (from Aiba et al., 2003 )

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Figure 3

Postulated changes in substrate metabolism as a function of enzyme and transporter inhibition and induction (adapted from Benet et al., 2003 )

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Figure 3

Postulated changes in substrate metabolism as a function of enzyme and transporter inhibition and induction (adapted from Benet et al., 2003 )

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Figure 4

Theoretical pharmacokinetic modifications in an induction or inhibition process

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Figure 4

Theoretical pharmacokinetic modifications in an induction or inhibition process

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Figure 5

Illustration of the digoxin-drug interaction case

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Figure 5

Illustration of the digoxin-drug interaction case

References

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Tables

Drug Interactions during Anti-Infective Treatments

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Table 1

Extent of decrease in fluoroquinolone Cmax and AUC when coprescribed with a gastroprotective drug a

Table 1

Extent of decrease in fluoroquinolone Cmax and AUC when coprescribed with a gastroprotective drug a

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Table 2

Behavior of antiproteases vis-à-vis CYP3A4 and P-gp

Table 2

Behavior of antiproteases vis-à-vis CYP3A4 and P-gp

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Table 3

Distribution of substrates, enzyme inducers, and enzyme inhibitors according to the different CYPs

Table 3

Distribution of substrates, enzyme inducers, and enzyme inhibitors according to the different CYPs

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Table 4

Substrates for CYP isoforms

Table 4

Substrates for CYP isoforms

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Table 5

Hepatic and intestinal distributions of the isoforms CYP3A4, -2D6, and -3A9 in the rat a

Table 5

Hepatic and intestinal distributions of the isoforms CYP3A4, -2D6, and -3A9 in the rat a

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Table 6

Inhibition of the metabolism of theophylline

Table 6

Inhibition of the metabolism of theophylline

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Table 7

Multiplication factor of the half-life of theophylline in combination with an FQ

Table 7

Multiplication factor of the half-life of theophylline in combination with an FQ

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Table 8

Drug interaction involving macrolides and ketolides

Table 8

Drug interaction involving macrolides and ketolides

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Table 9

Decrease in CYP activity according to Child-Pugh score

Table 9

Decrease in CYP activity according to Child-Pugh score

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Table 10

Decrease in CYP activity according to the presence or absence of cholestasis

Table 10

Decrease in CYP activity according to the presence or absence of cholestasis

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Table 11

Relative levels of P-gp in CNS and GI tract on Western immunoblot of FVB mouse from days 0 to 21 of life

Table 11

Relative levels of P-gp in CNS and GI tract on Western immunoblot of FVB mouse from days 0 to 21 of life

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Table 12

CYP enzyme activity in infants (1 to 28 days) as a fraction of adult activity

Table 12

CYP enzyme activity in infants (1 to 28 days) as a fraction of adult activity

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Table 13

Urinary excretion of glucuronidation and sulfatation activities for paracetamol

Table 13

Urinary excretion of glucuronidation and sulfatation activities for paracetamol

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Table 14

Antipyrine half-life in different populations

Table 14

Antipyrine half-life in different populations

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Table 15

Influence of environmental chemicals, social drugs, and life habits on epithelial cell transporter capacity and CYP enzyme activity

Table 15

Influence of environmental chemicals, social drugs, and life habits on epithelial cell transporter capacity and CYP enzyme activity

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Table 16

Substrates usually used as specific CYP probes

Table 16

Substrates usually used as specific CYP probes

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Table 17

Suggested gender differences in selected drug transporters and metabolizing enzymes

Table 17

Suggested gender differences in selected drug transporters and metabolizing enzymes

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Table 18

AUC increases over baseline of 13 different drugs when administered with grapefruit juice

Table 18

AUC increases over baseline of 13 different drugs when administered with grapefruit juice

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Table 19

Mean urinary recovery of pefloxacin and main metabolites after oral administration of a single dose of pefloxacin a

Table 19

Mean urinary recovery of pefloxacin and main metabolites after oral administration of a single dose of pefloxacin a

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Table 20

Species-dependent toxic effects of chemicals

Table 20

Species-dependent toxic effects of chemicals

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Table 21

Species defects in common metabolic reactions

Table 21

Species defects in common metabolic reactions