Drug release metabolic activity

Infants and children older than 1 year of age are considered to be very efficient metabolizers of drugs and may actually require larger doses than those predicted by weight adjustment of adult doses or shorter dosing intervals [33], On the basis of metabolic activity, sustained-release formulations would appear to be ideal for children 1-10 years old, if bioavailability issues prove not to be problematic. The ability to clear drugs in critically ill children may be severely compromised therefore, dosing in this subgroup of patients requires careful titration [34]. 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

Sodium nitroprusside is not an active hypotensive drug until metabolized to its active metabolite, NO, the mechanism of action of which has been previously described (Fig. 29.1). Studies with sodium nitroprusside suggest that it releases NO by its interaction with glutathione or with sulfhydryl groups in the erythrocytes and tissues to form a S-nitrosothiol intermediate, which spontaneously produces NO, which in turn freely diffuses into the VSM, thereby increasing intracellular cGMP concentration (6,9). NO also activates K channels, which leads to hyperpolarization and relaxation. 

C. Pharmacokinetics. Carbamazepine is slowly and erratically absorbed from the gastrointestinal tract, and peak levels may be delayed for 6-24 hours, particularly after an overdose (continued absorption for up to 96 hours has been reported with extended-release preparations). It is 75-78% protein bound with a volume of distribution (Vd) of approximately 1.4 LAg (up to 3 Ukg after overdose). Up to 28% of a dose is eliminated in the feces, and there is enterohepatic recycling. The parent drug is metabolized by r ochrome P-450, and 40% is converted to its 10,11-epoxide, which is as active as the parent compound. The elimination half-life is variable and is subject to autoinduction of P-450 enzymes the half-life of carbamazepine is approximately 18-55 hours (initially) to 5-26 hours (with chronic use). The half-life of the epoxide metabolite is approximately 5-10 hours. 

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