Assessment of Intestinal Availability (F_G) of Substrate Drugs of Cytochrome P450s by Analyzing Changes in Pharmacokinetic Properties Caused by Drug–Drug Interactions

Abstract

In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F G , the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F G from changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of F G values for 20 substrate drugs of CYP3A was 0.56 6 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 6 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates F G separating from the absorption ratio (F A ) although it requires approximation of F A . Since preciseness of approximation of F A does not greatly affect the evaluation of F G by the DDI method, we proposed a reasonable approximation method of F A for the evaluation of F G in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable.

Systematic and quantitative assessment of the effect of chronic kidney disease on CYP2D6 and CYP3A4/5

“…F a F g or F g values were calculated with one of the following methods (in the order of preference, depending on the data available) for CYP3A4/5 drugs that had clinical CKD reports ( Table ): IV/PO method: F a F g = F / [1−CL iv,B × (1−f e,urine ) / Q h ], where CL iv,B , f e,urine , F, and Q h represent blood clearance after intravenous administration, fraction eliminated into urine as an unchanged drug, absolute bioavailability, and hepatic blood flow rate, respectively (25.5 ml/min/kg). If the blood‐to‐plasma concentration ratio was not reported, this value was predicted using GastroPlus v. 9.0 (Simulations Plus, Lancaster, PA). An F g estimation method proposed by Hisaka et al , which utilizes changes in both AUC and terminal half‐life with DDI to differentiate the inhibitor effects on hepatic and intestinal CYP3A4/5. …”

“…Among the remaining 33 drugs, F a F g values of 22 drugs were estimated either by the intravenous/oral (IV/PO) method. Because of the instability in estimating F g with Method 2 for high clearance drugs, we estimated F g value only for 5 out of remaining 11 drugs with the method of Hisaka et al, 29 for which observed oral clearance was lower than hepatic blood flow rate. In total, F a F g or F g were calculated for 29 drugs.…”

Notable Drug–Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19

“…The apparent total body clearance (CL/F) was calculated by dividing the dosage of etizolam (0.25 mg/person) by AUC ∞ , and the apparent volume of distribution (V d /F), was calculated by dividing CL/F by k e . Intestinal availability (F g ) was estimated by the following equation: …”

“…Parameters indicated with an asterisk are in the presence of DDI. F* ag was estimated as reported, and 21.4 mL/min/kg was used as the value of Q H .…”

A New Physiologically Based Pharmacokinetic Model for the Prediction of Gastrointestinal Drug Absorption: Translocation Model

“…Metabolic intrinsic clearance, membrane permeability, and the blood-free fraction were taken from the literature (Gertz et al, 2011). The observed F G was estimated using the drug-drug interaction method reported by Hisaka et al (2014) and taken from other sources (Varma et al, 2010). The other observed or reported values required for analysis in this study are shown in Tables 3 and 4.…”