Download Chapter 14 Review Question Answers

Chapter 14 Review Question Answers
1.
Pregabalin possesses a similar isobutyl side to the essential amino acid L-leucine and
therefore has much better bioavailability than gabapentin for binding to small neutral
amino acid transporters for GI absorption and for crossing into the brain.
2.
An individual lacking SSADH cannot further metabolize SSA into succinic acid. The
SSA accumulated is reduced by nonselective alcohol dehydrogenase into a neuroactive
substance, γ-hydroxybutyric acid, which in turn may induce seizures.
3.
The attachment of an electron negative fluorine atom to the C-2 carbon of valproic acid
molecule would avert its metabolism via β-oxidation and thus prevents formation of the
toxic metabolite, (E)-2, 4-diene-VPA from 4-ene-VPA. The reason for this observation is
that a carbon fluorine bond is very strong, and therefore abstraction of an electron
negative fluorine atom would not be possible. The inductive effect of the fluorine atom
may also retard the formation of 4, 5-epoxy VPA, the other possible toxic metabolite of
VPA.
4.
Valrocemide lacks inhibitory activity toward epoxide hydrolase because it was found to
undergo amide hydrolysis to valproyl glycine rather than peptide bond cleavage to VPA
and glycine, as originally expected. The parent molecule may be too big to fit into the
VPA binding site on the enzyme to produce any inhibitory activity similar to VPA.
Valrocemide also lacks the teratogenicity of VPA because it is not a substrate for the
CYP isozymes at the clinically relevant concentrations.
5.
Valproate is a potent inhibitor of epoxide hydrolase and UDP-glucuronyl transferase (the
enzymes needed for the glucuronidation of many drug molecules). Inhibition of epoxide
hydrolase by valproate prolongs the biological half-life of the arene oxide intermediate
and thus increases phenytoin-induced idiosyncratic toxicities. The formation of catechol
metabolites from p-HPPH or m-HPPH intermediates also increases due to the inability to
excrete them as their O-glucuronides. Thus, a further increase in the risk of
hepatotoxicity and idiosyncratic toxicities would also be expected if the level of catechol
exceeds the detoxification capacity of COMT in the liver or kidneys (due to an increase
in the formation of the reactive o-quinones from these catechols). Thus, the two possible
reactive metabolites are the arene-oxide and the o-quinone shown in Figure 3 of this
paper.
6.
Idiosyncratic reaction of aromatic AEDs is due to the formation of heptens via the
alkylations of cellular proteins with their reactive arene oxides or the o-quinone
intermediates that produce antibodies after the first exposure. Phenytoin, fosphenytoin,
phenobarbital, and primidone are all aromatic AEDs that have similar aromatic rings;
thus, all will be recognized by these antibodies on subsequent exposure, thereby
producing cross hypersensitivity.
Ch. 14 Review Question Answers
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7.
In the presence of a specific inhibitor of CYP3A4, such as ketoconazole, normal
metabolic conversion of CBZ to the inactive 10, 11-CBZ-diol pathway is blocked. In this
situation, the carbamazepine would be expected to metabolize through the minor
metabolic pathway, catalyzed by CYP2C9 and CYP2C19. Thus, hydroxylation of either
of the aromatic rings and formation of the toxic metabolites arene oxide, catechol, and oquinone would also be expected.
8.
Both carbamazepine and phenytoin induce UDP-glucuronyl transferase, the major
metabolic enzyme responsible for deactivating lamotrigine.
9.
In the presence of a CYP3A4 inhibitor, felbamate is degraded by the CYP2E1 isozymes
to give the expected hydroxylated metabolites, 2-OH-FBM and pOH-FBM. Thus, an
inhibitor of either CYP3A4 or CYP2E1 has little or no effect on felbamate metabolic
biotransformations. However, an inducer of either of these isozymes definitely increases
the formation of the hydroxylated metabolites, thereby enhancing renal clearance of
felbamate.
10.
Valproic acid is primarily deactivated by -oxidation to its inactive metabolite, 3-ketoVPA. Since felbamate is known to inhibit mitochondrial -oxidation, a decrease in the
dosing of VPA may be needed to prevent side effects associated with overdose of VPA.
It is also possible that, in the presence of felbamate, more toxic 4,5-epoxy VPA may be
produced via microsomal oxidation catalyzed by CYP isozymes.
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