Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

Abstract

Isoniazid (INH), introduced in the 1950s, continues to be one of the most safe and cost-effective agents used to treat tuberculosis (9). Because of the increasing incidence of tuberculosis that has resulted from the coepidemic of human immunodeficiency virus infection (32), the use of INH in the prevention (9, 17) and treatment (9) of tuberculosis is on the rise. INH is often given chronically to critically ill patients who are on multiple medications to treat tuberculosis and AIDS-related mycobacterial disease (18, 45), raising the potential for adverse drug-drug interactions.In humans, INH has been found to decrease the clearance of several drugs, including phenytoin (see, e.g., references 3, 24, and 30), carbamazepine (54, 58, 59), diazepam (36), triazolam (37), vincristine (7), primidone (48), and acetaminophen (10, 35), sufficiently to require a reduction of the dose or discontinuation of INH. Upon consideration of the primary metabolic pathways of the drugs affected and the enzymes catalyzing them, many of these drug-drug interactions appear to be attributable to pharmacokinetic changes that can be understood in terms of alterations of multiple hepatic drug metabolic pathways catalyzed by the cytochrome P450 (CYP450) system (2). In fact, the ability of INH to inhibit the hepatic CYP450 system in vitro in rat liver microsomes has been described (25,34). In animals (6), it has been shown that INH effectively inhibits para-hydroxylation of phenytoin in vivo. Despite the strong link between INH drug interactions and inhibition of the CYP450 system and despite its widespread use for more than 4 decades, our knowledge is incomplete with respect to which specific CYP450 isoforms are inhibited, making prediction of drug interactions with INH difficult. The only isoform that has been studied in detail in human and animal models is CYP2E1, for which INH has been reported to have a biphasic effect (induction and inhibition) (8). This property of INH may explain the increased risk of hepatotoxicity of coadministered compounds (e.g., ethanol and acetaminophen) (10,33,35), but it is unlikely to explain the clinically documented interactions with other drugs, as most of them appear to be catalyzed by CYP isoforms other than CYP2E1 (e.g., phenytoin by CYP2C9 and CYP2C19 and carbamazepine by CYP3A and CYP2C8 [2,28]).In order to enable physicians to improve predictions about which drugs might interact with INH, the present study was undertaken to evaluate the inhibitory potency of INH on six common human drug-metabolizing CYP450 isoforms in vitro.

Inhibitory Effect of Antituberculosis Drugs on Human Cytochrome P450-Mediated Activities

“…It is considered to be caused by the inhibition of CYP (11 -14). In a recent publication, Desta et al have reported that INH was a potent inhibitor of CYP2C19 (competitive) and CYP3A (noncompetitive) in human liver microsomes (HLM) (13). Wen et al also showed the inhibition of CYP1A2, CYP2A6, CYP2C19, and CYP3A4 activities by INH, and they further suggested that these effects were increased by the preincubation of INH with HLM at 37°C for 15 min in the presence of NADPH (14).…”

“…The report showed that the combination use of INH and PZA increased the adverse reaction induced by phenytoin, whose metabolism is mainly mediated by CYP2C9 (15 -17). Considering the minor inhibitory effect of INH on CYP2C9 activity as described by Desta et al (13), it was predicted that the observed inhibition might be caused by PZA. Furthermore, the inhibitory effect of PZA on CYPmediated metabolic activities has been also reported in rats (18).…”

Treatment of Comorbid Tuberculosis and Depression

“…However, the available literature indicates that there are some similarities in the metabolism of isoniazid and certain SSRIs. 22,29,30,35 Although no substantial clinical evidence indicates that the combination of isoniazid and SSRIs is harmful, available evidence indicates that some SSRIs might be a better choice than others for concurrent treatment. Citalopram appears to be metabolized primarily by CYP2C19 and/or CYP3A4, both of which are inhibited by isoniazid, and thus it might not be the best choice for a patient taking isoniazid.…”

“…While it has not been definitively established which isoenzymes are implicated in the metabolism of isoniazid, CYP2E1, CYP1A2, CYP2C9, CYP2C19, and CYP3A are inhibited to varying degrees by isoniazid (Table 4). 29,30 In a study employing human liver microsomes, Desta et al 30 indicated that CYP2C19 and CYP3A were inhibited potently by isoniazid in a concentration-dependent manner. Both enzymes were inhibited approximately 40% by doses in the therapeutic range.…”

Drogas antituberculose: interações medicamentosas, efeitos adversos e utilização em situações especiais - parte 1: fármacos de primeira linha

“…This inhibitory effect of isoniazid can increase the plasma concentrations of certain drugs to toxic levels. (3,36) The plasma concentrations of anticonvulsants, such as phenytoin and carbamazepine, can increase when these drugs are used in combination with isoniazid. (37) The same occurs with the benzodiazepines that are metabolized by oxidation (e.g., diazepam and triazolam), as well as with theophylline, valproic acid, disulfiram, acetaminophen, and oral anticoagulants.…”