Factors affecting the steady state drug/metabolite conc ratio (Cont'd)
f- Metabolite volume of distribution
Examine the drug and metabolite conc-time profiles during multiple drug administratior of different drugs that form metabolites with different Vd(m). (All other parameters are similar)
The change in the metabolite Vd does not affect the steady state concentration of the drug or the metabolite. So, the drug/metabolite concentration ratio at steady state does not change.
CLTis the total body clearance of the drug (volume/time).
Vd is the volume of distribution of the drug (volume).
fmis the fraction of drug dose converted to the metabolite (unitless).
CLT(m) is the total body clearance of the metabolite (volume/time).
Vd(m)is the volume of distribution of the metabolite (volume).
Metabolite volume of distribution:
- Repeated administration of the same dose of different drugs will achieve the same average steady state conc if the clearance is similar. In this case the metabolite formation rate at steady state will be similar if fm is the same.
- When the formation rate of the metabolite and the metabolite clearance are similar, the s.s. metabolite conc will be the same. So, the drug to metabolite conc ratio will be the same at steady state.
- Metabolites with larger Vd have longer half life if the clearance is the same. Notice the slower rate of approaching the steady state for the metabolites with larger Vd.
Volume of distribution
The volume of distribution is the apparent volume in which the drug can distributed in. It is the parameter that relates the amount of drug in the body to the concentration of the drug in the sampling site. It is not an actual volume, however it is a hypothetical volume determined by the drug distribution behavior.
The volume of distribution ranges from 3-5 liters to more than 25 L/kg. Drugs with higher affinity for tissues, have higher volume of distribution.
