Primidone
T l/2: 6-22 hours
Vd: 0.5-1.0 L/kg
Fb: 0
pKa: ?
Occurrence and Usage. Primidone (Mysoline), a desoxy derivative of phenobarbital, was synthesized in 1949 and first evaluated as an anticonvulsant in 1952. It is used frequently for the treatment of grand mal and temporal lobe seizures, in daily oral doses of 250-1500 mg. The drug is supplied as the free acid in tablets of 50 and 250 mg and as a 250 mg/5 mL suspension for oral administration.
Blood Concentrations. A single 250 mg oral dose of primidone given to 10 patients who were not receiving other anticonvulsants produced an average peak serum primidone concentration of 4.9 mg/L at 4 hours. Primidone concentrations declined with an average half-life of 15 hours (range, 9-22) in these patients, but patients receiving other anticonvulsant drugs exhibited primidone half-lives averaging 8 hours. The metabolites phenylethylmalonamide and phenobarbital were present at detectable levels within 24 or 48 hours, respectively, of the single primidone dose (Cloyd et al., 1981). After a 500 mg oral dose, one subject achieved a peak serum primidone concentration of about 8 mg/L within 5 hours, while phenylethylmalonamide and phenobarbital concentrations remained below 2 mg/L for at least 24 hours (Gallagher et al., 1972).
Steady-state plasma primidone concentrations were found to correlate well with the chronic daily primidone dose when it was varied over a range of 250-1250 mg; a dose of 500 mg produced an average plasma concentration of 6.7 mg/L (range, 1-14) while 1250 mg gave a concentration of 14.7 mg/L (range, 1019) (Booker et al., 1970). Patients receiving 1000 mg of the drug daily exhibited serum primidone concentrations of 11-15 mg/L, phenobarbital concentrations of 17-29 mg/L, and phenylethylmalonamide concentrations of 7-10 mg/L (Bielmann et al., 1974). The plasma half-life of primidone is relatively short compared to its metabolites phenobarbital (3-4 days) and phenylethylmalonamide (29-36 hours) (Gallagher and Baumel, 1972).
Metabolism and Excretion. Primidone is metabolized primarily by oxidative cleavage to phenylethylmalonamide, with a small amount being oxidized to phenobarbital. Although phenobarbital is a minor metabolite, its long half-life results in its accumulation in plasma during chronic primidone therapy. The concurrent administration of phenytoin, an enzyme inducer, produces much higher phenobarbital concentrations than those seen in patients receiving primidone alone (Fincham et al., 1974).
Primidone and metabolically-produced phenobarbital may account for nearly all of the anticonvulsant activity of primidone, since phenylethylmalonamide is a relatively poor anticonvulsant (Baumel et al., 1973). However, a recent study in rats showed that seizure protection correlated best with the summed serum concentrations of phenylethylmalonamide and phenobarbital (Albertson et al., 1980).
During chronic administration of primidone, approximately 92% of the dose is eliminated in the 24-hour urine; 42% is found as primidone, 45% as phenylethylmalonamide and 5% as phenobarbital, its hydroxy metabolites and their conjugates (Kauffman et al., 1977).
Toxicity. Primidone intoxication is manifested by weakness, ataxia, vertigo, nystagmus, drowsiness, nausea, and vomiting. A patient on chronic therapy with primidone developed these symptoms and was found to have serum concentrations of 4 mg/L for primidone, 126 mg/L for phenylethylmalonamide, and 94 mg/L for phenobarbital. Serum half-lives for the latter two substances were about 8 days each, substantially longer than in normal subjects (Stern, 1977).
Patients who survived massive acute ingestion of primidone have exhibited maximal serum concentrations of 97-300 mg/L for primidone, 68-155 mg/L for phenylethylmalonamide, and 25-77 mg/L for phenobarbital. The half-lives for the drugs were within the normal ranges for therapeutic doses. A finding common to all such patients was crystalluria, due to precipitation of unchanged drug in urine (Bailey and Jatlow, 1972; Lagenstein et al., 1977; Matzke et al., 1981; van Heijst et al., 1983).
In contrast, a nonfatal suicide attempt involving a 10-year-old epileptic patient resulted in serum concentrations of 95 and 175 mg/L for primidone and phenobarbital, respectively, about 12 hours after ingestion; the corresponding urine concentrations were 1570 and 50 mg/L, respectively (Cate and Tenser, 1975). The high phenobarbital concentrations observed in this case are probably a result of both enzyme induction and pre-existing drug due to prior treatment with primidone.
A case of fatal overdosage with primidone in an adult who was not under therapy with the drug was reported in which the blood primidone concentration was 65 mg/L and phenobarbital, 3 mg/L (Wright, 1975).
Analysis. Several gas chromatographic procedures have been reported that are capable of measuring primidone and its two metabolites simultaneously in plasma. Baumel and others (1972) described a method in which primidone and phenylethylmalonamide were converted to trimethylsilyl derivatives, and phenobarbital, which does not form a stable silyl derivative, was analyzed underivatized in a second injection. A single-injection analysis described by Couch et al. (1973) involved a treatment of a sample extract with diazomethane, yielding the dimethyl derivative of phenobarbital without affecting primidone or phenylethylmalonamide. Other authors performed the analysis without derivatization on columns with mixed liquid phases (Thoma et al., 1978; Streete and Berry, 1987). Liquid chromatography is well-suited to the simultaneous assay of these 3 drugs (Kabra et al., 1978).
Many analysts consider it sufficient to measure only primidone and phenobarbital concentrations, and this is easily accomplished with most comprehensive anticonvulsant assays.