The utility of a specific hepatic CYP-3A4 probe (C14-Erythromycin breath test [EBT]) versus the general CYP-P450 probe (antipyrine clearance [ACL] test), for the prediction of docetaxel (D) pharmacokinetics (PK)

2523 Background: BSA-based cytotoxic dosing does not account for the individual variability in drug disposition. In the case of D, CYP 3A4 probes such as the EBT have been assessed to individualise dosing, but inconsistently. This report is the first study comparing the EBT directly with the widely available general P450 probe, the ACL test, for the prediction of D PK when given either q 21 days or weekly. Methods: Patients (pts) with pre-treated advanced malignancy suitable for D therapy, Se bilirubin≤1.0xUNL, AST≤1.5xUNL & ALP≤2.5xUNL, were entered. Prior to D therapy, pts underwent EBT and ACL test. Pts were given IV 14C N-methyl-erythromycin and exhaled breath samples were captured for 14CO2 from 5–120 mins post. The EBT parameters determined: 14CO2 flux at 10 min (CO2f10), & 20 min (CO2f20), (iii) terminal rate constant kCO2 (iv) AUCCO2,(0-∞) & AUCCO2,(0–60). For the ACL test, pts was given oral antipyrine 10mg/kg, blood samples were collected from 0, 4 & 24 hrs post, and serum levels measured: ACL was calculated as per Farrell et al.(Br J Clin Pharmacol 18:559). D was given 75mg/m2 q21 days or 35mg/m2 weekly. Samples taken for D PK in course 1 day 1, parameters included: half life (tD1/2), & clearance (CLD). Correlations were sought between EBT parameters, ACL values and D PK parameters. Results: 20 pts accrued, M:F= 12:8, Median age= 65. Mean BSA = 1.77m2 (1.44–2.07). D q21 days:D weekly= 13:7. EBT parameters (N= 19) (Mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min- 1) 0.007 (22), AUCCO2,(0-∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). ACL (N=19) (ml/min); 35.8 (37). No significant differences observed for EBT parameters and ACL between the q21 days vs weekly dosing. D PK parameters (N=19): CLD (l/hr) 57.2 (36), tD1/2 (hrs) 12.7 (33). No correlations were observed between the D PK and EMBT parameters for all pts and regardless of the regimen given. For D weekly pts, a significant linear relationship was observed between CLD and ACL (P =0.007, R2= 79.47%). Conclusions: The utility of EBT for the prediction of D PK was not confirmed in this study. The Antipyrine Clearance test may be superior in this regard for D, but regimen dependent and hence warrants further evaluation. No significant financial relationships to disclose.

Decreased Antipyrine Clearance following Endotoxin Administration: In Vivo Evidence of the Role of Nitric Oxide

ABSTRACT Klebsiella pneumoniae endotoxin has been found to decrease hepatic P450-mediated drug-metabolizing enzyme activity in a time-dependent manner. In this study, we investigated the role of nitric oxide (NO) in the decrease in hepatic drug-metabolizing enzyme activity caused by endotoxin in vivo. We measured in vivo pharmacokinetic parameters of antipyrine in rats treated with endotoxin and/or a selective inhibitor of inducible NO synthase (iNOS),S-methylisothiourea. Intraperitoneal injection of endotoxin (1 mg/kg of body weight) dramatically decreased the systemic clearance of antipyrine, reflecting reduced hepatic drug-metabolizing enzyme activity, and significantly increased the level of nitrite and nitrate (NOx) in the plasma. S-Methylisothiourea (10 mg/kg) reversed this decreasing antipyrine clearance and reduced the level of NOx in plasma. Repeated injections of an NO donor, (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK-409; 10 mg/kg), at a dose which maintained plasma NOx at the same levels as those caused by endotoxin injection, also decreased the systemic clearance of antipyrine. These findings suggest that the overproduction of NO observed in this animal model is at least partially responsible for the significant reduction in the hepatic drug-metabolizing enzyme activity that may happen in a gram-negative bacterial infection.