Inhibition of metabolism

Following concurrent administration of two drugs, especially when they are metabolized by the same enzyme in the liver or small intestine, the metabolism of one or both drugs can be inhibited, which may lead to elevated plasma concentrations of the dtug(s), and increased pharmacological effects. The types of enzyme inhibition include reversible inhibition, such as competitive or non-competitive inhibition, and irreversible inhibition, such as mechanism-based inhibition. The clinically important examples of drug interactions involving the inhibition of metabolic enzymes are listed in Table 1 [1,4]. 

The mechanism of action for liver toxicity and carcinogenicity may involve the formation of reactive products (Bonse and Henschler 1976 Bonse et al. 1975 Fisher et al. 1991 Larson and Bull 1992b). Methods for reducing the destructive damage caused by these intermediates, or for blocking their formation through inhibition of metabolic pathways may prove effective in reducing hepatic toxicity but are not currently available for clinical use. 

Methylated derivatives of 7-methylB[a]A are particularly carcinogenic when substitutes in the 7-, 12-, or 6- and 8-positions (152,153). The increased carcinogenicity of these compounds may result from the inhibition of metabolism at the 8-11 positions which increases the amounts of bay region diol epoxides formed, the greater reactivity of such epoxides with DNA, or an intrinsic difficulty for cells to repair such adducts (154). 

Flodstrom, S., L. Wamgard, S. Ljungquist, and U.G. Ahlborg. 1988. Inhibition of metabolic cooperation in vitro and enhancement of enzyme altered foci incidence in rat liver by the pyrethroid insecticide fenvalerate. Arch. Toxicol. 61 218-223. 

Stehly, G.R. and W.L. Hayton. 1989. Disposition of pentachlorophenol in rainbow trout (Salmo gairdneri) effect of inhibition of metabolism. Aquat. Toxicol. 14 131-148. 

When CYP2E1 was inhibited by intraperitoneal injection of DCE, levels of exhaled -hexane increased approximately 25-fold within 4 hours and returned to pre-dose levels at approximately 24 hours, closely paralleling the inhibition and resynthesis time-course for CYP2E1. No increase in lipid peroxidation was observed, indicating that the increase in exhaled -hexane was the result of inhibition of metabolism. It is probable that many P-450 isoforms are capable of hydroxylating -hexanc (both in vivo and under laboratory conditions) it is not possible at this time to specify which forms are definitely involved in -hexane metabolism in vivo. 

Ibrahim et al. 1963). Aiken and Braitman (1989) determined that cyanide has a direct effect on neurons not mediated by its inhibition of metabolism. Consistent with the view that cyanide toxicity is due to the inability of tissue to utilize oxygen is a report that in cyanide-intoxicated rats, arterial p02 levels rose, while carbon dioxide levels fell (Brierley et al. 1976). The authors suggested that the low levels of carbon dioxide may have led to vasoconstriction and reduction in brain blood flow therefore, brain damage may have been due to both histotoxic and anoxic effects. Partial remyelination after cessation of exposure has been reported, but it is apparent that this process, unlike that in the peripheral nervous system, is slow and incomplete (Hirano et al. 1968). The topographic selectivity of cyanide-induced encephalopathy may be related to the depth of acute intoxication and distribution of blood flow, which may result in selected regions of vascular insufficiency (Levine 1969). 

Kurata M, Hirose K, Umeda M. 1982. Inhibition of metabolic cooperation in Chinese hamster cells by organochlorine pesticides. Gann 73 217-221. 

Inhibition of metabolic pathway Sulfonamides Sulfamethoxazole Efflux Altered target... 

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

In conjunction with the discussion of the receptor assay system, it is logical to discuss the variations of the plate assay systems and/or growth systems using colorimetric indicators of inhibition of metabolism or growth. 

When data are available to enable comparison of the plasma concentration time profile after single administration with that after repeated administration, this would enable determination of whether the substance has time dependent kinetics (due to induction of metabolism, inhibition of metabolism, and/or accumulation and saturation of processes involved in distribution, metabohsm, and excretion). 

Nonlinearity in toxicokinetics can be assessed by comparing relevant parameters, e.g., AUC, after different dose levels, or after single and repeated exposure. Dose dependency may be indicative of saturation of enzymes involved in the metabolism of the compound. An increase of AUC after repeated exposure as compared to single exposure may be an indication for inhibition of metabolism. A decrease in AUC may be an indication for induction of metabohsm. 

Do not administer concurrently with cisapride, midazolam, triazolam, or ergot derivatives. Competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, respiratory depression see Drug Interactions). 

SSRIs—fluvoxamine, fluoxetine, and paroxetine, more than sertraline and citalopram Inhibition of metabolism at CYP2D6 isoenzyme TCA toxicity due to up to 10-fold increase in TCA levels with coadministration Lower TCA dose Baumann, 1996... 

Oral contraceptives Inhibition of metabolism at CYP2D6 isoenzyme Possible TCA toxicity increased amount of active TCA varies can be up to 30% Lower TCA dose D Arcy, 1986... 

Cimetidine Inhibition of metabolism at CYP2D6 isoenzyme Sudden TCA toxicity No coadministration Henauer and Hollister, 1984... 

Dexedrine, methylphenidate Inhibition of metabolism at 2D6 enzyme seen in vitro Potential TCA toxicity, none reported in literature Currently theoretical interaction only Fawcett, 2000... 

Elmore, E., Korytynski, E.A. Smith, M.P. (1985) Tests with the Chinese hamster V79 inhibition of metabolic cooperation assay. Prog. Mutat. Res., 5, 597-612 Environmental Protection Agency (1984) Guidelines establishing test procedures for the analysis of pollutants under the Clean Water Act. Final Rule and Interim Final rale and Proposed Rule. Fed. Reg., 49, 43234-43312... 

Loprieno, N., Boncristiani, G, Forster, R. Goldstein, B. (1985) Assays for forward mutation in Schizosaccharomycespombe strain PL Prog. Mutat Res., 5, 297-306 Lutz, W.K. (1986) Investigation of the potential for binding of di(2-ethylhexyl) phthalate (DEHP) to rat liver DNA in vivo. Environ. Health Perspect., 65, 267-269 Malcolm, A.R. Mills, L.J. (1989) Inhibition of gap-jnnctional intercellular communication between Chinese hamster lung fibroblasts by di(2-ethylhexyl) phthalate (DEHP) and trisodinm nitrilotriacetate monohydrate (NTA). Cell Biol. Toxicol., 5, 145-153 Malcolm, A.R., Mills, L.J. McKeima, E.J. (1983) Inhibition of metabolic cooperation between Chinese hamster V79 cells by tnmor promoters and other chemicals. Ann. N.Y. Acad. Set, 407, 448-450... 

Scott, J.K., Davidson, H. Nelmes, A.J. (1985) Assays for inhibition of metabolic cooperation between mammalian cells in culture. In Ashby, J., de Serres, F.J., Draper, M., Ishidate, M., Jr, Margolin, B.H., Matter, B.E. Shelby, M.D., eds, Progress in Mutation Research, Volume 5, Evaluation of Short-Term Tests for Carcinogens. Report of the International Programme on Chemical Safety s Collaborative Study on in vitro assays, Amsterdam, Elsevier Science, pp. 613-618... 

Inhibition of metabolism of endogenous activator-Hncreased activator-Hncreased effect... 

Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism. No other important drug interactions have been reported for the succinimides. 

Metabolism inducible. Susceptible to inhibition of metabolism by CYP2C9. Highly bound to plasma proteins. Anticoagulation response altered by drugs that affect clotting factor synthesis or catabolism. 

Induction of hepatic microsomal drug-metabolizing enzymes. Susceptible to inhibition of metabolism, primarily by CYP3A4. 

Susceptible to inhibition of metabolism by CYP3A4 inhibitors. High cisapride serum concentrations can result in ventricular arrhythmias. 

Figure 5.3d The metabolism of the drug terfenadine. The double lines indicate the inhibition of metabolism by other drugs such as ketoconazole or the natural product found in grapefruit juice. This leads to a rise in the blood level of the drug and toxicity.

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