First order to zero order in therapeutic range

 **With increase in dose rate, plasma concentration of the drug also increases.

·        **In first order kinetics, as the plasma concentration increases, the rate of elimination also increases.

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**So, there is a direct relationship between dose rate and plasma concentration ( linear relation)

·         **The process of metabolism and elimination are carried out by enzymes and transporters.

·        ** Most enzymes and transporters  in the body obey saturation kinetics.

·         **So theoretically, all drugs will show first order kinetics at low concentration in plasma and zero order kinetics at high concentration in plasma.

·        ** However, in clinical pharmacology, we are concerned only about the therapeutic range because the dose and dose interval are planned to keep the drug concentration in the therapeutic range.

·         **So, drugs for which the enzymes and transporters are yet not saturated in therapeutic range are said to obey first order kinetics. And drugs for which the enzymes are saturated in therapeutic range are said to obey zero order kinetics.

Fo**For drugs like phenytoin, the enzymes and transporters become saturated from non-saturated state in the therapeutic range, and the elimination kinetics also change from the first order to zero order in the therapeutic range.

**So if we plot a graph between dose rate and plasma concentration, it will be linear and less steep in the initial phase (first order kinetics), but steeply rising in the later phase (zero order kinetics)