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Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution.

ABSTRACT: Many mathematical models for in vitro to in vivo prediction of drug-drug interactions (DDIs) of orally administered victim drugs have been developed. However, to date, none of these models have been applicable to all intravenously administered victim drugs. We derived and conducted a sensitivity/error analysis of a modification to the existing multiple mode interaction prediction model such that it is applicable to all intravenously administered victim drugs. Using this model we showed that ignoring the hepatic extraction ratio (EH) (as low as 0.3) of intravenously administered victim drugs can result in 1) substantial underestimation of f(m, CYPi) (the fraction of hepatic clearance of the victim drug via a given enzymatic pathway) and 2) error in dissecting the contribution of intestinal and hepatic components of DDIs for orally administered drugs. Using this model we describe DDI boundaries (degree of inhibition or induction) at which ignoring the EH of commonly used victim drugs results in ?30% error in the predicted area under the concentration-time curve (AUC) ratio or contribution of intestinal interaction to a DDI (CYP3A probes only). For the most widely used victim drug midazolam, these boundaries for AUC ratio are net inhibition (I/K(i) or ?/k(deg)) ?1.3 or fold induction ?2.1; for intestinal contribution the boundaries are 0.37 and 1.5, respectively. To accurately predict the intravenous AUC ratio, intestinal contribution, or f(m, CYPi) 1) for all induction DDIs irrespective of EH of the victim drug and 2) for modest to potent inhibition DDIs even when the EH is moderate (?0.3), we propose that our model be used.

SUBMITTER: Kirby BJ

PROVIDER: S-EPMC2967394 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution.

Kirby Brian J BJ Unadkat Jashvant D JD

Drug metabolism and disposition: the biological fate of chemicals 20100819 11

Many mathematical models for in vitro to in vivo prediction of drug-drug interactions (DDIs) of orally administered victim drugs have been developed. However, to date, none of these models have been applicable to all intravenously administered victim drugs. We derived and conducted a sensitivity/error analysis of a modification to the existing multiple mode interaction prediction model such that it is applicable to all intravenously administered victim drugs. Using this model we showed that igno ...[more]

PMID: 20724498

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Project description:We analysed the importance of systemic and peripheral arteriovenous O2 difference ( a-v¯O2 difference and a-vf O2 difference, respectively) and O2 extraction fraction for maximal oxygen uptake ( V˙O2max ). Fick law of diffusion and the Piiper and Scheid model were applied to investigate whether diffusion versus perfusion limitations vary with V˙O2max . Articles (n = 17) publishing individual data (n = 154) on V˙O2max , maximal cardiac output ( Q˙max ; indicator-dilution or the Fick method), a-v¯O2 difference (catheters or the Fick equation) and systemic O2 extraction fraction were identified. For the peripheral responses, group-mean data (articles: n = 27; subjects: n = 234) on leg blood flow (LBF; thermodilution), a-vf O2 difference and O2 extraction fraction (arterial and femoral venous catheters) were obtained. Q˙max and two-LBF increased linearly by 4.9-6.0 L · min-1 per 1 L · min-1 increase in V˙O2max (R2 = .73 and R2 = .67, respectively; both P < .001). The a-v¯O2 difference increased from 118-168 mL · L-1 from a V˙O2max of 2-4.5 L · min-1 followed by a reduction (second-order polynomial: R2 = .27). After accounting for a hypoxemia-induced decrease in arterial O2 content with increasing V˙O2max (R2 = .17; P < .001), systemic O2 extraction fraction increased up to ~90% ( V˙O2max : 4.5 L · min-1 ) with no further change (exponential decay model: R2 = .42). Likewise, leg O2 extraction fraction increased with V˙O2max to approach a maximal value of ~90-95% (R2 = .83). Muscle O2 diffusing capacity and the equilibration index Y increased linearly with V˙O2max (R2 = .77 and R2 = .31, respectively; both P < .01), reflecting decreasing O2 diffusional limitations and accentuating O2 delivery limitations. In conclusion, although O2 delivery is the main limiting factor to V˙O2max , enhanced O2 extraction fraction (≥90%) contributes to the remarkably high V˙O2max in endurance-trained individuals.

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Dataset Information

Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution.

Publications

Impact of ignoring extraction ratio when predicting drug-drug interactions, fraction metabolized, and intestinal first-pass contribution.

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