Page 85 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 4 Drug Biotransformation 71

TABLE 4–5 Partial list of drugs that enhance drug TABLE 4–6 Partial list of drugs that inhibit drug
metabolism in humans. metabolism in humans.
Drugs Whose Metabolism Is Drug Whose Metabolism Is
Inducer Enhanced Inhibitor 1 Inhibited
Benzo[a]pyrene Theophylline Allopurinol, chloramphenicol, Antipyrine, dicumarol,
isoniazid probenecid, tolbutamide
Carbamazepine Carbamazepine, clonazepam,
itraconazole Chlorpromazine Propranolol
Chlorcyclizine Steroid hormones Cimetidine Chlordiazepoxide, diazepam,
warfarin, others
Ethchlorvynol Warfarin
Dicumarol Phenytoin
Glutethimide Antipyrine, glutethimide,
warfarin Diethylpentenamide Diethylpentenamide
Griseofulvin Warfarin Disulfiram Antipyrine, ethanol, phenytoin,
warfarin
Phenobarbital and other Barbiturates, chloramphenicol,
barbiturates 1 chlorpromazine, cortisol, Ethanol Chlordiazepoxide (?), diazepam (?),
coumarin anticoagulants, methanol
desmethyl imipramine, digitoxin, Grapefruit juice 2 Alprazolam, atorvastatin,
doxorubicin, estradiol, cisapride, cyclosporine,
itraconazole, phenylbutazone, midazolam, triazolam
phenytoin, quinine, testosterone
Itraconazole Alfentanil, alprazolam, astemizole,
Phenylbutazone Aminopyrine, cortisol, digitoxin
atorvastatin, buspirone, cisapride,
Phenytoin Cortisol, dexamethasone, cyclosporine, delavirdine,
digitoxin, itraconazole, diazepam, digoxin, felodipine,
theophylline indinavir, loratadine, lovastatin,
midazolam, nisoldipine, pheny-
Rifampin Coumarin anticoagulants, digi-
toxin, glucocorticoids, itracon- toin, quinidine, ritonavir, saqui-
navir, sildenafil, simvastatin,
azole, methadone, metoprolol,
oral contraceptives, prednisone, sirolimus, tacrolimus, triazolam,
verapamil, warfarin
propranolol, quinidine, saquinavir
Ritonavir 2 Midazolam Ketoconazole Astemizole, cyclosporine,
terfenadine
St. John’s wort 3 Alprazolam, cyclosporine,
digoxin, indinavir, oral contra- Nortriptyline Antipyrine
ceptives, ritonavir, simvastatin, Oral contraceptives Antipyrine
tacrolimus, warfarin
Phenylbutazone Phenytoin, tolbutamide
1 Secobarbital is an exception. See Table 4–6 and text. Ritonavir Amiodarone, cisapride,
2
With chronic (repeated) administration; acutely, ritonavir is a potent CYP3A4 itraconazole, midazolam,
inhibitor/inactivator. triazolam
3
For a more comprehensive list of drugs whose metabolism is enhanced by St. John’s
wort, see Rahimi and Abdollahi, 2012; Russo et al, 2014; and Tsai et al, 2012. Saquinavir Cisapride, ergot derivatives,
midazolam, triazolam
Secobarbital Secobarbital
Thus, continued use of some drugs may result in a pharmacokinetic
type of tolerance—progressively reduced therapeutic effectiveness Spironolactone Digoxin
due to enhancement of their own metabolism. Troleandomycin Theophylline,
Conversely, simultaneous administration of two or more drugs methylprednisolone
may result in impaired elimination of the more slowly metabo- 1 While some inhibitors are selective for a given P450 enzyme, others are more general
lized drug and prolongation or potentiation of its pharmacologic and can inhibit several P450s concurrently.
2
Active components in grapefruit juice include furanocoumarins such as 6′,
effects (Table 4–6). Both competitive substrate inhibition and 7′-dihydroxybergamottin (which inactivates both intestinal and liver CYP3A4) as well
irreversible substrate-mediated enzyme inactivation may aug- as other unknown components that inhibit P-glycoprotein-mediated intestinal drug
ment plasma drug levels and lead to toxic effects from drugs with efflux and consequently further enhance the bioavailability of certain drugs such as
cyclosporine. For a more comprehensive list of drugs whose metabolism is inhibited
narrow therapeutic indices. Indeed, such acute interactions of by grapefruit juice furanocoumarins, see Bailey et al, 2013.
terfenadine (a second-generation antihistamine) with a CYP3A4
substrate-inhibitor (ketoconazole, erythromycin, or grapefruit led to withdrawal or restricted use of the 5-HT agonist cisapride.
4
juice) resulted in fatal cardiac arrhythmias (torsades de pointes) Similarly, allopurinol both prolongs the duration and enhances
requiring its withdrawal from the market. Similar DDIs with the chemotherapeutic and toxic actions of mercaptopurine by
CYP3A4 substrate-inhibitors (such as the antibiotics erythro- competitive inhibition of xanthine oxidase. Consequently, to
mycin and clarithromycin, the antidepressant nefazodone, the avoid bone marrow toxicity, the dose of mercaptopurine must be
antifungals itraconazole and ketoconazole, and the HIV protease reduced in patients receiving allopurinol. Cimetidine, a drug used
inhibitors indinavir and ritonavir) and consequent cardiotoxicity in the treatment of peptic ulcer, has been shown to potentiate