Metabolism-Based Drug-Drug Interactions: What Determines Individual Variability in Cytochrome P450 Induction?

Abstract

ABSTRACT:Individual variability in cytochrome P450 (P450) induction comprises an important component contributing to the difficulties in assessing and predicting metabolism-based drug-drug interactions in humans. In this article, we outline the major factors responsible for the individual variability in P450 induction, including variable transporter activity and metabolism of inducers in vivo, genetic variations of P450 genes and their regulatory regions, genetic variations of receptors and regulatory proteins required for induction, and different physiological and environmental elements. With a better understanding of the major determinants in P450 induction and a profile of the phenotypes of these determinants in each individual, it is believed that the individual variability in induction-mediated drug-drug interactions can be adequately evaluated.

Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients

“…Given that both the maximum concentrations and AUC increased, this may reflect either increased bioavailability or decreased metabolism. Competitive inhibition of enzyme binding sites or variability in drug transporters, such as P-glycoprotein or the organic anion transporting polypeptide family of enzymes, may account for the differences we found (33,42). Our study was not designed to explore the mechanisms of the interaction between nevirapine and lumefantrine.…”

Metabolism of [D10]Phenanthrene to Tetraols in Smokers for Potential Lung Cancer Susceptibility Assessment: Comparison of Oral and Inhalation Routes of Administration

“…Beginning with the work of Conney and coworkers in the 1960s (Welch et al, 1968) and continuing to the present, these studies have used a variety of in vitro approaches, most commonly using mitogen-activated human lymphocytes to investigate the inducibility of PAH metabolism via the aryl hydrocarbon receptor, which regulates the CYP1A1, CYP1A2, and CYP1B1 genes, coding for cytochromes P450 1A1, 1A2, and 1B1, which are TABLE 2 Levels of urinary ͓D 10 ͔PheT, total ͓D 9 ͔HOPhe, and the ratios of ͓D 10 ͔PheT/͓D 9 ͔HOPhe and natural PheT/HOPhe in subjects 1, 6, and 14 (with high ͓D 10 ͔PheT formation) and 12, 7, and 2 (with low ͓D 10 ͔PheT formation) a Total ͓D 9 ͔HOPhe ϭ ͓D 9 ͔1-HOPhe ϩ ͓D 9 ͔2-HOPhe ϩ ͓D 9 ͔3-HOPhe ϩ ͓D 9 ͔4-HOPhe. jpet.aspetjournals.org involved in PAH metabolism (Nebert et al, 2004;Tang et al, 2005). Approximately 10% of the white population has a high inducibility phenotype.…”

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

“…Certainly, polymorphisms in both the regulatory and coding regions of the CYP genes affect the degree of induction of cytochrome P450 enzymes by drugs. 31 This may also be a potential mechanism for the induction of multidrug resistance through PGP upregulation. To complicate matters further, (a) induction of PGP by drugs is tissue-dependent, and this may have some bearing upon the relevance of particular inducers in the study of drug resistance in different diseases 32 ; and (b) it is also possible that baseline or constitutive expression levels may determine the maximal degree of induction that occurs in response to contact with an environmental inducer.…”