Primidone metabolism

Carbamazepine Phenytoin Primidone Signs of toxicity possible after addition of phenytoin owing to concomitant increase in plasma phenobarbital concentrations in some patients Induction of primidone metabolism phenytoin may inhibit the clearance of metabolically derived phenobarbital... 

Sutton G, Kupfeibeig HJ Isoniazid as an inhibitor of primidone metabolism. Neurology (1975) 25,1179-81... 

Fincham RW, Schottelius DD, Sahs AL. The influence of diphenylhydantoin on primidone metabolism. Trans Am Neurol Assoc 9iy)9Z, 197-9. 

Schmidt D. The effect of phen3d oin and ethosuximide on primidone metabolic in patients... 

Porro MG, Kupferberg HJ, Porter RJ, Theodore Newmark ME. Phen3doin an inhibitor and inducer of primidone metabolism in an epileptic patient BrJ C wP/ianwaco/(1982) 14, 294-7. 

Anticonvulsants Anticonvulsants were one of the first groups of drugs for which TDM was indicated. The common anticonvulsants encountered in clinical practice are phenobarbitone, primidone (metabolized to phenobarbitone), phenytoin, carbamazepine, ethosuximide, and valproate. The majority of assays for these drugs are immunoassays these days as 24 h availability of measurements of these drugs has become the general expectation. 

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

The anticonvulsant primidone (1035) resembles phenobarbital but lacks the 2-oxo substituent. It was introduced in 1952 and has remained a valuable drug for controlling grand mal and psychomotor epilepsy. As might be expected, primidone is metabolized to yield phenobarbital (1034 X = 0) and C-ethyl-C-phenylmalondiamide (1036), both of which have marked anticonvulsant properties however, primidone does have intrinsic activity and an appropriate mixture of its metabolites has only a fraction of its activity (73MI21303). Primidone may be made in several ways, of which desulfurization by Raney nickel of the 2-thiobarbiturate (1034 X = S) or treatment of the diamide (1036) with formic acid (at 190 °C) seem to be the most satisfactory (54JCS3263). 

B3a. Baker, H., Frank, O., Hutner, S. H., Aaronson, S, Ziffer, H., and Sobotka, H., Lesions in folic acid metabolism induced by Primidone. Experientia 18, 224-226... 

The anticonvulsant agent primidone (4.246) is the 2-dihydro derivative of phenobarbital (4.247), which is one of its metabolites. The second major metabolite, 2-ethyl-2-phenylmalondiamide (4.248), is produced by a double C-N cleavage [160]. The profile of plasma levels in rats strongly suggests that 2-ethyl-2-phenylmalondiamide is not derived from the metabolite phenobarbital, but directly from primidone. Indeed, a C(2)-hydroxylated metabolite serves as an intermediate for both detected metabolites (see also Chapt. 6 in [21]). N-Alkyl derivatives of primidone yield a greater proportion of ring-opened metabolites, an observation explained by their higher susceptibility to oxidative metabolism at C(2) [161]. 

Olesen, 0. V., and Dam, M., The metabolic conversion of primidone (Mysoline) to phenobarbitone in patients under long-term treatment. Acta Neurol. Scand. 43, 348-356 (1967). 

Miscellaneous Primidone Tonic-clonic Psychomotor Focal 20 to 25 Metabolized to PB and PEMA, both active... 

Primidone is an other second line barbiturate used orally to control tonic-clonic and partial seizures. It is a pro-drug as it is metabolized to phenobarbital and phenylethylmalonamide (PEMA), however both the parent compound as well as the metabolites have anti seizure activity. Its use is more difficult to monitor and adverse effects occur even more frequently than with phenobarbital. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Valproic acid causes hair loss in about 5% of patients, but this effect is reversible. Transient gastrointestinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primidone, benzodiazepines, or other CNS depressant agents. 

Phenobarbital and primidone are quite similar both chemically and pharmacologically, and much of the anticonvulsant activity of primidone may be ascribed to its metabolic conversion to phenobarbital. As would be expected in such a case, the clinical indications for the two compounds are very similar. There is some indication that primidone may be more effective in the treatment of partial seizures with complex symptoms, but the evidence is not compelling. 

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by microsomal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvulsant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced. 

Lamotrigine is metabolized by glucuronidation, possibly by the UGT 1A4 system. As such, it is vulnerable to other UGT inducers—oral contraceptives, phenytoin, carbamazepine, phenobarbital and primidone, and to a UGT inhibitor, valproate (Hachad et ah, 2002). 

Valproate metabolism may be induced by other anticonvulsants, including carbamazepine, phenytoin, primidone, and phenobarbital, resulting in an increased total clearance of valproate and perhaps decreased efficacy. 

CBZ stimulates the CYP-450 enzyme system, increasing clearance of concomitantly prescribed drugs also metabolized by this system ( 377). Thus, the dose of these medications may need to be increased to maintain efficacy (372). Levels of CBZ may also be influenced by other hepatically metabolized, co-prescribed drugs. VPA, isonicotine, hydrazine, and erythromycin are some of the agents that can increase CBZ levels, while agents such as phenytoin and primidone can lower them. Table 10-25 summarizes the potentially clinically significant interactions between CBZ and other commonly co-prescribed medications ( 379, 380). 

Primidone, or 2-desoxyphenobarbital (Figure 24-6), was first marketed in the early 1950s. It was later reported that primidone was metabolized to phenobarbital and phenylethylmalonamide ( ). All three compounds are active anticonvulsants. 

Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form (Figure 24-6). Both primidone and phenobarbital also undergo subsequent conjugation and excretion. 

Levetiracetam Action on synaptic protein SV2A Well absorbed orally not bound to plasma proteins metabolized to 3 inactive metabolites ty2 6-11 h Generalized tonic-clonic seizures, partial seizures, generalized seizures Toxicity Nervousness, dizziness, depression, seizures Interactions Phenobarbital, phenytoin, carbamazepine, primidone... 

Primidone [NP] Increased estrogen metabolism possible reduction in oral contraceptive efficacy. 

Primidone has a relatively short half-life (4-15 hours), but it is metabolized to phenobarbitone and phenylethylmalonamide, which prolongs the duration of the anticonvulsant effect. 

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