Vaoproic
Acid (Depakote®, Depakene®)
· Valproic acid (VPA) is an established antiepileptic drug with a simple chemical structure but an unusually broad spectrum of action. It is generally well tolerated but has two rare side effects (i.e., hepatotoxicity and teratogenicity). These drawbacks are apparently shared by its equipotent metabolite, (E)-2-propyl-2-pentenoic acid (2-ene VPA).
· Metabolism of VPA is very complex and is the result of hepatic microsomal oxidation and glucuronidation. At least 10 metabolites have been identified. The major urinary metabolite is 2-propyl-3-keto-pentanoic acid. Other minor metabolites identified are the hydroxylated or their dehydrated products, and 2-propylglutaric acids. All of these metabolites are excreted as glucuronides.
· The hepatotoxicity of VPA is most likely associated with 2,4-diene-VPA and/or 4-epoxy-VPA. It should be noted that 2,4-diene-VPA is normally detoxified as a cysteine conjugate via GSH/ glutathione transferase metabolic pathway while 4-epoxy-VPA is deactivated by epoxy hydrolase to form diol. It should be pointed out that these toxic metabolites may also react with the SH group or other nucleophiles on the cellular proteins thereby forming covalently bonded heptens. These drug-modified proteins then elicit and become the target of an immune response.
· 2-Propyl-4-pentynoic acid, an analog of valproic acid with a triple bond in the terminal carbon, has been shown to cause teratogenic side effects in laboratory animals. Thus, it is reasonable to assume that both of the above mentioned toxic metabolites could also be responsible for the teratogenic effect of VPA.
· The Valproic acid is known to inhibit hepatic glucuronidase and epoxide hydrolase. (See further discussion on this topic under antiepileptic drug interactions).
Study Questions:
1. Explain chemically/biochemically why 2-fluoro-VPA, a synthetic analog of VPA currently clinical trials, may not possess similar hepatotoxic/teratogenic side effects as VPA.
2. 4-Methyl-2-n-propyl-4-pentenoic acid and 2-isobutyl-4-pentenoic acids are said to lack the inhibitory activity of VPA toward epoxide hydrolase. Provide a possible chemical rationale for this observation.
· The principal metabolic pathway of Phenytoin and Phenobarbital in human is aromatic hydroxylation, catalyzed by the cytochrome P-450 isozymes (CYP2C9 and CYP2C19). The reactive intermediate, arene oxide is deactivated by either epoxide hydrolase to dihydrodiol or by the action of glutathione (GSH) and glutathione transferase. The pathways of phenytoin metabolism are depicted below.
· Hypersensitivity reactions (idiosyncratic toxicity) to the aromatic AEDS in the susceptible individuals are believed to stem from the reactions of these reactive intermediates (i.e., arene oxide catechol or o-quinone) with hepatic enzymes or other cellular proteins forming covalently bonded haptens.
· It has also been suspected that these reactive arene oxides or epoxides mediate the teratogenicity of phenytoin and other AEDS. Recent studies indicated that epoxide hydrolase might be useful as biomarker for prenatal determination of risk of the fetal hydantoin syndrome.
· Both phenytoin and phenobarbital are potent liver enzyme inducers.
Study Questions:
1. Explain why co-administering valproate with carbamazepine or phenytoin will increase their idiosyncratic toxicities.
2. Explain why there are cross-sensitivities among phenytoin, phenobarbital, and carbamazepine?
3. Phosphenytoin is the disodium phosphate ester of 3-hydroxymethyl-5, 5-diphenylhydantoin. It is a prodrug of phenytoin. Explain chemically how it is converted into phenytoin in vivo?
4. What enzyme is responsible for the formation of the 3-O-methylcatechol metabolite of phenytoin?
· The major metabolic pathway of carbamazepine (CBZ) is the formation of the stable 10,11-CBZ epoxide by cytochrome P-450 isozyme CYP3A4. This reactive metabolite is further deactivated by the action of epoxide hydrolase to give inactive 10,11-CBZ-diol that is excreted as glucuronides.
· Several other minor metabolites have also been identified with CBZ. These are derived from the reactive intermediate, arene oxide by CYP2C9/19. Further metabolic conversions of this intermediate lead to the formations of 2(3)-hydroxy-CBZ, CBZ-2, 3-diol, CBZ-catechol, and CBZ-o-quinone in a similar manner as in phenytoin. [You should practice drawing the chemical structures for each of these metabolites].
· It should be pointed out that carbamazepine, similar to phenobarbital and phenytoin, is a potent liver enzyme inducers. Furthermore, it will also induce its own metabolic biotransformations.
Study questions:
1. Explain, with your knowledge of how drugs are metabolized, why oxcarbazine (see structure on page 1 of this handout) possesses fewer side effects and also appears to be less likely to induce liver enzymes than CBZ?
2. What will be the expected metabolic profiles of CBZ if a specific inhibitor of CYP3A4 such as ketoconazole, an antifungal drug or the flavones present in grapefruit is taken concurrently?
Lamotrigine
(Lamictal®)
· Lamotrigine, an antiepileptic drug of the phenyltriazine class, is metabolized predominantly by glucuronidation. The major inactive urinary metabolites isolated are a 2-N-glucuronide (76%) and a 5-N-glucuronide (10%). The aromatic ring is deactivated by the presence of chlorine atoms toward aromatic oxide formation.
· Coadministration of lamotrigine with valproic acid greatly enhances the incidence of idiosyncratic reactions. It is conceivable that in the presence of valproic acid (an inhibitor of glucuronidase enzyme) the concentration of the reactive arene oxide intermediate may be increased due to the reduced capacity of glucuronidase to metabolize lamotrigine.
Study questions:
1. Explain why lifarizine (see structure on page 1) has a better pharmacological/toxicological profiles than lamotrigine?
2. Explain why lamotrigine is eliminated more rapidly in patients who have been taking carbamazepine or phenytoin?
Primidone
(Mysoline®)
· Primidone is metabolized by CPY2C9/19 to phenobarbital and phenylethylmalonamide (PEMA). Both of these metabolites have anticonvulsant activities. However, it is generally believed that the pharmacological action of primidone is due mainly to the minor metabolite, phenobarbital. Thus, primidone is much less potent/toxic than phenobarbital since most of the drug is rapidly degraded to the less potent metabolite, PEMA. The pathways of primidone metabolism are depicted below.
Gabapentin
(Neurontin®)
· Gabapentin is a unique drug because it is not metabolized in humans and has very little liability for causing metabolic-based drug-drug interaction, particularly with other AEDs. Greater than 95% of the drug is excreted unchanged by the kidney.
· Gabapentin and two of its closely related analogues, (S)-3-isobutyl-GABA and cis- (1S, 3R)-1-aminomethyl-3-methylcyclohexylacetic acid (see their structures on page 1 of this handout) are readily transported into the brain due to their structural similarity to the essential amino acid, L-leucine.
· Both of these analogues are more potent than gabapentin as an anticonvulsant (> 10 times). This increase in anticonvulsant potency could conceivably be due to their ability to inhibit the biosynthesis of the neurotransmitter, L-glutamic acid at the presynaptic nerve terminals of the NMDA receptors (i.e., competes with L-leu for binding to the transaminase enzyme).
Study Questions:
1. Explain why (S)-3-isobutyl-GABA has a shorter duration of action than gabapentin? Draw a possible metabolite for this drug.
2. Cis- (1S, 3R)-1-aminomethyl-3-methylcyclohexylacetic acid is said to have a superior pharmaco-kinetic profile to gabapentin. Explain.
.Topiramate (Topamax®)
· Topiramate is a sulphamate-substituted monosaccharide. It is a derivative of the naturally occurring sugar D-fructose.
· It has good oral bioavailability of 85-95%, most likely due to its structural similarity to D-glucose. Thus, it is actively transported into the brain by the D-glucose transporter. [Recall that D-fructose and D-glucose have identical stereochemistry at many of their chiral centers]
· Only about 20% of the drug is eliminated by hepatic metabolism (CYP2C19), the remaining drugs are excreted unchanged by the kidney. The sulphamate ester is hydrolyzed by sulfatase to the corresponding primary alcohol, which is further oxidized to the corresponding carboxylic acid.
Tiagabine
(Gabitril®)
· > 90% of tiagabine is metabolized by CYP3A4 isozymes. The primary site of metabolic attacks is the methyl group on the thiophen rings. Thus, benzylic oxidation of the methyl by CYP3A4 produces a hydroxymethyl (-CH2OH) metabolite, which is excreted either as an o-glucuronide or further oxidized to the corresponding carboxylic acid (-COOH) metabolite.
Felbamate
(Felbatol®)
· Felbamate is a carbamate ester of 2-phenyl-1, 3-propanediol. The carbamate ester is stable to esterase and therefore provides good oral bioavailability.
· The sites of metabolic attack are the benzylic carbon (i.e., benzylic hydroxylation via the CYP3A4/2E1to give the major metabolite) and para position on the aromatic ring (i.e., p-aromatic hydroxylation via the CYP2C19 to give the minor metabolite).