+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants

, : Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. Drug Metabolism and Pharmacokinetics 28(5): 411-415

Inhibition of cytochrome P450 (CYP) 3A4 is the major cause of drug-drug interactions (DDI). We have previously reported that the genetic variation of CYP3A4 significantly affected the inhibitory profiles of typical competitive inhibitors. In addition to competitive inhibition, some clinically significant DDI are attributable to mechanism-based inhibition (MBI). However, the differences in the MBI kinetics among CYP3A4 genetic variants remain to be characterized. In this study, we quantitatively investigated the inhibition kinetics of MBI inhibitors, erythromycin and clarithromycin, on the CYP3A4 variants CYP3A4.1, 4.2, 4.7, 4.16, and 4.18. The activity of CYP3A4 was assessed using testosterone 6β-hydroxylation with recombinant CYP3A4. Both erythromycin and clarithromycin decreased the activity of CYP3A4 in a time-dependent manner. The maximum inactivation rate constants, k(inact,max), of erythromycin for CYP3A4.2 and CYP3A4.7 were 0.5-fold that for CYP3A4.1, while that for CYP3A4.16 and CYP3A4.18 were similar to that for CYP3A4.1. The K(I) values of erythromycin for CYP3A4.2, 4.7, 4.16, and 4.18 were 1.2-, 0.4-, 2.2- and 0.72-fold those of CYP3A4.1, respectively. Similar results were obtained for clarithromycin. In conclusion, the inhibitory profiles of MBI inhibitors, as well as competitive inhibitors, may possibly differ among CYP3A4 variants. This difference may contribute to interindividual differences in the extent of DDI based on MBI.


PMID: 23514827

Other references

Stevens, J.T.; Hall, L.L.; Farmer, J.D.; DiPasquale, L.C.; Chernoff, N.; Durham, W.F., 1977: Disposition of 14C and/or 74As-cacodylic acid in rats after intravenous, intratracheal, or peroral administration. The distribution, excretion and possible metabolism of (14)C- and/or (74)As-cacodylic acid was studied in rats following a single intravenous injection, intratracheal instillation or oral gavage. Male Sherman rats were dosed at levels ranging from...

Cowey A.; Ellis C.M., 1969: The cortical representation of the retina in squirrel monkey and rhesus monkeys and its relation to visual acuity. Experimental Neurology 24(3): 374-385

Miyake, Y.; Iwai, T.; Sugai, M.; Miura, K.; Suginaka, H.; Nagasaka, N., 1991: Incidence and characterization of Staphylococcus aureus from the tongues of children. Three hundred and seven children who had no diseases other than dental diseases other than dental disease were examined for their oral carriage of Staphylococcus aureus, the most common persistent human pathogen. Eighty-four percent of them were p...

Anonymous, 2006: Adacel and Boostrix: Tdap vaccines for adolescents and adults. Medical Letter on Drugs and Therapeutics 48(1226): 5-6

Daemen, J.; Feyz, L.; Van Zandvoort, L.; Van Mieghem, N.M., 2017: Redo renal denervation using a multi-electrode radiofrequency system in patients with persistent therapy-resistant hypertension. Renal sympathetic denervation has been studied as a potential therapeutic option for patients with therapy-resistant hypertension; however, a significant proportion of patients do not show a significant reduction in blood pressure and are class...

Lembke, W.D.; Jones, B.A.J., 1972: Selecting a method for scheduling irrigation, using a simulation model. A water-balance model was used to simulate an irrigation system, in order to compare 3 irrigation scheduling practices on 2 soils for maize in central Illinois. For soil with a water-holding capacity of 0.8 in/ft, the practice of applying 30% of t...

Robakis N.K.; Ramakrishna N.; Wolfe G.; Wisniewski H.M., 1987: Molecular cloning and chromosomal localization of the nucleic acid sequences encoding the cerebrovascular and plaque amyloid peptide. Federation Proceedings 46(6): 2038

Mayhew, T.M., 2007: Taking tissue samples from the placenta: an illustration of principles and strategies. Tissue samples are removed from placentas for a variety of reasons associated with a host of investigative techniques, including chorionic villus sampling, villus explant culture, cell culture, proteomic analysis, gene expression profiling, micros...

Radó, J.P.; Gercsák, G.; Bános, C., 1984: Relationships between glucose-induced elevation of serum potassium in the upright posture, hormonal changes and renal functions in captopril-treated hypertensives. Hormone and Metabolic Research 16(1): 57-57

Baren, J.H.V.V.n; Bomer, W., 1979: Procedures for the collection and preservation of soil profiles. Methods of taking and impregnating soil profiles, and the storage and display of lacquer peels and soil monoliths are described, with two appendices including 29 photographs and details of the chemicals used.