Antiepileptic Drugs, 5th Edition

Phenobarbital and Other Barbiturates


Chemistry, Biotransformation, and Pharmacokinetics

Gail D. Anderson PhD

Professor, Department of Pharmacy, University of Washington, Seattle, Washington


Phenobarbital is 5-ethyl-5-phenylbarbituric acid, a substituted barbituric acid with a molecular weight of 232.23 (Figure 51.1). The free acid of phenobarbital is a white crystalline material with a melting point of 176°C. Phenobarbital is only sparingly soluble in water (1 g in 1000 mL). In addition to the low aqueous solubility, phenobarbital also has a relatively low lipid solubility. It is soluble in organic solvents such as chloroform (1 g in 40 mL), diethylether (1 g in 15 mL), and ethanol (1 g in 10 mL). The sodium salt is freely soluble in water and is used in the formulations for intravenous or intramuscular administration (1).

Phenobarbital is a weak acid with a negative log of dissociation constant (pKa) of 7.3, approximately the same as physiologic pH. Therefore, changes in the ratio of ionized to nonionized phenobarbital that occur within the normal range of physiologic pH (7.35 to 7.45) can alter both the distribution and the excretion of the drug (Table 51.1).



After oral and intramuscular administration, the absorption of phenobarbital is essentially complete, with greater than 95% bioavailability (1, 2, 3). The time to peak plasma concentrations after oral administration ranges from 0.5 to 4 hours (1, 2, 3, 4, 5). Peak concentrations appear 2 to 8 hours after an intramuscular injection (1,3). Rectal administration of phenobarbital sodium parenteral solution resulted in a mean bioavailability of 90% and a time to peak concentration of 4.4 hours (6).

In a group of newborn infants given a single dose of phenobarbital, the time to peak concentrations ranged from 1.5 to 6 hours (7). Absorption of phenobarbital was delayed in a group of malnourished children compared with healthy children (5.6 hours versus 1.0 hour); however, the maximum concentration obtained was not different, a finding suggesting no differences in bioavailability (8).

Administration of activated charcoal can be used to decrease the equilibrium of phenobarbital across the gastrointestinal tract in cases of overdose. Several studies have demonstrated an increase in total body clearance and reduction of the elimination half-life (t½) of phenobarbital by a factor of two-to 10-fold with the administration of charcoal (9,10, 11, 12, 13).

Formulations and Routes of Administration.

Phenobarbital is available in tablets, capsules, extentabs, elixir, and a parenteral formulation for oral, rectal, intramuscular, and intravenous routes of administration.


After intravenous administration, phenobarbital distributes into the body in two phases, which can be characterized by a two-compartmental mathematical model (1,2,14). Studies in animals have demonstrated that the early distribution includes liver, kidney, and heart. During the late phase, phenobarbital distributes to brain, muscle, and intestine. The average volume of distribution of phenobarbital ranges from 0.54 to 0.73 L/kg in adults (1,15,16). Newborns and young infants have a larger average volume of distribution, ranging from 0.8 to 1 L/kg (17, 18, 19, 20, 21, 22, 23). This corresponds to a relatively larger extracellular fluid volume in neonates (24). In older infants and children, the average volume of distribution is similar to that in adults, ranging from 0.57 to 0.70 L/kg (7,25,26). Because of the low lipid solubility, phenobarbital does not distribute into fat, and loading doses of phenobarbital are usually calculated using ideal body weight or lean body mass (27). However, a case report suggested that using ideal body weight to calculate the loading


dose in a patient whose total body weight was greater than 300% ideal body weight significantly underestimated the loading dose needed to provide therapeutic plasma concentrations of phenobarbital (28).


FIGURE 51.1. The main biotransformation pathways of phenobarbital.

Plasma Protein Binding.

Phenobarbital is approximately 55% bound to albumin in adults (4,29, 30, 31) and children (30,32). In neonates, phenobarbital binding is reduced, presumably because of relatively low albumin concentrations at birth; binding is 57% to 64% in neonates without hyperbilirubinemia and 70% to 72% in neonates with hyperbilirubinemia (30,33). No data are available regarding protein binding in the elderly patient population, in whom an age-related decline in albumin often occurs (34).





Tmax (hr)


V (L/kg)

Fraction Bound (%)

Half-life (hr)

Clearance (mL/hr/kg)



p.o.: 1.5-6






7, 21, 23, 24, 25, 75, 94, 95, 96

Infants (1-12 mo)

0.6 ± 0.07

63.2 ± 4.2






55 (46-63)



7, 25, 32, 97, 108

Adults: monotherapy

p.o. 0.5-4
i.m. 2
Rectal: 4.4



47 (41-56)



1, 2, 3, 4, 5, 6, 14, 29, 71, 88, 91

Adults: polytherapy with inducers

48 ± 0.5



1, 4

Children: polytherapy with inducers

6.8 (5.6-8.0)

93, 97

Adults: polytherapy with valproate





71, 88

Children: polytherapy with valproate

5.0 (4.0-6.0)





Liver disease



130 ± 15




Acute hepatitis


104 (60-127)


F, bioavailability; Tmax, time to maximum plasma concentration; V, volume.

aValues reported as mean ± standard deviation and/or range in different populations.

Cerebrospinal Fluid, Brain, and Other Tissues.

Cerebrospinal fluid (CSF) concentrations of phenobarbital are similar in infants and adults. In infants, CSF levels are 44% to 57% (7), and in adults, they are 43% to 60% (29,35) of plasma concentrations. Thus, CSF concentrations correlate with unbound phenobarbital serum levels (29). Brain penetration of phenobarbital is relatively slow. Animal studies have demonstrated that maximal entry takes 12 to 60 minutes (36, 37, 38). During prolonged status epilepticus, brain uptake is increased, presumably by disruption of the blood-brain barrier (39). The reported concentrations of phenobarbital in surgically removed human epileptic brain tissues relative to plasma concentrations vary from 0.35 to 1.13 (40, 41, 42,43). The brain:plasma phenobarbital concentration ratio in a group of newborns who died while receiving phenobarbital was 0.71±0.21 (19). The ratio of phenobarbital in gray to white matter ranged from 0.86 to 1.11 in this group of newborns, similar to values found in adults (40,42,43). In another group of 11 premature and full-term babies, infants, and children (44), the brain:serum phenobarbital concentration ratio was 0.82±0.22. Phenobarbital concentrations in brain were significantly less than other organs including liver, kidney, spleen, pancreas, and lung (44). A study that evaluated postmortem concentrations of phenobarbital in different regions of the brains from 39 patients with epilepsy determined that the concentrations of phenobarbital in all regions of the cortex and cerebellum were largely comparable (45). Phenobarbital concentrations in the frontal cortex were 1.4 times higher and 2.1 times higher than the total and unbound phenobarbital concentrations in serum, respectively.

Unbound phenobarbital distributes into saliva, with saliva:total phenobarbital serum concentration ratios ranging from 0.21 to 0.52 (32,35,46, 47, 48, 49, 50). Two studies have demonstrated that the distribution of phenobarbital into saliva depends on salivary pH (4,51); however, other studies have not found an effect of pH (32,50). In spite of the contradictory results, when equations incorporate the relative ratio of phenobarbital pKa to the salivary pH, there is an excellent correlation between salivary and unbound serum concentrations (4,51).

Transplacental Passage.

Phenobarbital distributes across the placenta and accumulates in fetal liver and brain (52, 53, 54). At the time of delivery, infants of mothers who have received phenobarbital have equivalent serum concentrations (55, 56, 57, 58, 59, 60, 61, 62, 63). In one of the studies, the placental passage of phenobarbital was evaluated in three groups of mothers and infants based on duration of phenobarbital treatment (63). Infants of mothers with epilepsy treated for 229±57 days, mothers treated for gestational hypertension and preeclampsia for 10±16 days, and mothers given prophylaxis of intraventricular hemorrhage in premature birth treated for 3.3±21 days were compared. Phenobarbital arterial cord concentrations were 100±2.8%, 89±21%, and 77±16% compared with the maternal concentrations for the three groups, respectively. In addition, a lower percentage of phenobarbital was found in infants with lower cord arterial pH values at birth.

Breast Milk.

Phenobarbital is secreted into breast milk, with concentrations in breast milk 30% to 40% of maternal serum concentrations (58,64). Phenobarbital is slowly eliminated by the infants, with resulting infant serum concentrations that may reach or exceed maternal concentrations (58,60,65). Excess sedation, poor suckling and bodyweight


gain, and a high incidence of vomiting have resulted in a recommendation by the American Academy of Pediatrics that phenobarbital be used with caution during lactation (66).


Phenobarbital is eliminated from the body by hepatic metabolism and renal excretion of unchanged drug.


In the liver, phenobarbital is metabolized to two major metabolites, p-hydroxyphenobarbital (PBOH), which partially undergoes sequential metabolism to a glucuronic acid conjugate, and 9-D-glucopyra-nosylphenobarbital, an N-glucoside conjugate (PNG). Minor metabolism includes a dihyrodiol, catechol, and p-methylcatechol (Figure 51.1).


Butler (67) first reported the formation of PBOH from phenobarbital in the dog, and it was later confirmed in humans (11,19,68,69) that PBOH was a major metabolite. A substantial fraction of the PBOH is then conjugated with glucuronic acid to form PBOH glucuronide. In studies in patients treated with phenobarbital, an average of 55% (range, 30% to 87%) of the PBOH found was excreted as the O-glucuronide (29,70,71).

There is a large intersubject variability in the fraction of the phenobarbital dose that is metabolized by aromatic hydroxylation to PBOH. Several single-dose studies have reported a range of 8% to 34% of the dose recovered in urine as total PBOH (70,72, 73, 74). Steady-state experiments found that 6% to 40% of the phenobarbital daily dose was total PBOH (70,71,75,76).

Kadar et al. (69) found a wide range of total PBOH excreted in four children (aged 4 to 15 years). Total PBOH accounted for a range of 4.4% to 32.1%, with 38% to 61% conjugated with glucuronic acid. There was no apparent correlation between the age of the child and the percentage of either total or conjugated PBOH. Boreus (75) found that in four neonates, 15% of the phenobarbital dose was total PBOH, with 33% conjugated with glucuronic acid. These authors concluded that the neonates had a decreased ability to conjugate PBOH. However, because of the lack of pharmacologic activity of PBOH, (67,77) this difference would not be clinically significant.


Glucosidation is an uncommon detoxication pathway in mammals; however, 9-D-glucopyra-nosylphenobarbital is a quantitatively significant metabolite of phenobarbital (PNG). Tang et al. (73) administered a mixture of 14C-labeled and 15N-labeled phenobarbital to two normal volunteers. Thin-layer chromatography of 16-day urine identified the N-glucoside conjugate of phenobarbital after comparison with a synthetic standard. In five volunteers, phenobarbital N-glucoside accounted for 26% (range, 24% to 30%) of the phenobarbital dose (39,40,73,74). Bhargava et al. (78) examined randomly collected urine samples from eight patients treated with phenobarbital monotherapy. PNG was detected in all but one patient. Bernus et al. (76) found 14% (range, 0% to 34%) excreted as PNG in 14 patients treated with phenobarbital.

In one study in four children, PNG accounted for 6% to 22.4% of the dose (69). Bhargava and Garrettson (79) also studied the development of phenobarbital metabolism in four neonates by analyzing serial single daily voided urines. The N-glucosidation pathway was not active at birth, and onset had not occurred until after 2 weeks of age. In one infant, by day 20, PNG accounted for 50% of the drug and metabolites in the urine sample. In the other infants, PNG was still not apparent when urine collections ended at days 14 and 16. Subsequent studies have demonstrated that PNG is subject to decomposition under physiologic conditions of temperature and pH. Unless the urine collected for analysis is acidified immediately before storage, decomposition may occur, and the percentage of PNG will be underestimated (80).

Minor Metabolites.

The phenobarbital epoxide could also spontaneously or enzymatically yield the corresponding dihydrodiol (Figure 51.1). Harvey et al.(81) were able to obtain gas chromatography-mass spectrometry evidence that the dihydrodiol was present in rat, guinea pig, and human urine in small amounts. Theoretically, oxidation of the dihydrodiol could yield the corresponding catechol. This substance has been tentatively identified in rat and human urine by gas chromatography-mass spectrometry analysis (82). The 4-hydroxy 3-methoxy derivative of phenobarbital (O-methylcatechol) has been isolated from human urine, and its structure was confirmed by comparison with a synthetic standard. In six normal volunteers who received a single dose of phenobarbital, approximately 1% of the dose was recovered as this metabolite (83).


Cytochrome P450 2C9 (CYP2C9) plays a major role in the metabolism of phenobarbital to PBOH with minor metabolism by CYP2C19 and CYP2E1 (84). There are no data on the identity of the uridine diphosphate glucuronosyltransferase enzyme that is responsible for the formation of PNG.


The effect of CYP2C19 polymorphism on the plasma clearance of phenobarbital was studied in a group of Japanese patients receiving phenobarbital treatment (85). Patients who were homozygous for the CYP2C19*3 or CYP2C19*2 genotype (the CYP2C19 poor metabolizers), had a 19% decreased clearance compared with the wild-type homozygous CYP2C19*1. There was also a trend of decreased plasma clearance in heterozygous extensive metabolizers compared with homozygous extensive metabolizers.



A set of twins exhibiting a genetic deficiency in the formation of the metabolite now known as amobarbital N-D-glucopyranoside has been reported (86), a finding suggesting that a deficiency in the enzymes responsible for the formation of PNG may also occur. There is also limited evidence that some patients do not form PNG. Of the three series of patients evaluated for urinary excretion of PNG, two identified patients without PNG. Bhargava et al. (78) identified one of seven patients and Bernus et al. (76) found two of 14 without detectable urinary excretion of PNG.

Biliary and Renal Excretion.

There is considerable intersubject and intrasubject variability in the amount of phenobarbital excreted unchanged in the urine. Single-dose studies (30,31,72, 73, 74,87) in which urine was collected for a minimum of 15 days reported a range of 9% to 33% (average, 23%) of the phenobarbital dose excreted as unchanged drug. Steady-state studies found that the fraction of the dose excreted unchanged in urine averaged 22% (range, 7% to 55%) in four different studies (70,71,76,88).

Boreus et al. (75) showed that the 8-day urinary excretion of unchanged phenobarbital after a single dose in four newborn infants (17%) was similar to that in two adult volunteers (16%). Similarly, in four critically injured children (ages 5, 7, 10, and 15 years), Kadar et al. (69) found a range of 17.8% to 23.1% excreted as unchanged drug.

The renal clearance of phenobarbital depends on both urine flow (29,70,71,89) and urine pH (89), resulting from the lipophilicity and pKa (7.3) of this drug. This phenomenon may explain some of the intersubject variability found in the fraction of dose excreted unchanged in urine. After a drug is filtered by the glomerulus and possibly is actively secreted into the tubule, it may be subject to passive reabsorption. Drug reabsorption takes place primarily in the distal tubule, where the tubule membranes favor the movement of lipid-soluble and un-ionized compounds. The efficient reabsorption of water from the proximal tubule and loop of Henle results in a large concentration gradient between drug in the distal tubule and drug in the plasma. Increasing urine flow decreases this concentration gradient, resulting in a decrease in passive reabsorption. Small changes in urine pH can cause large increases or decreases in the percentage of an un-ionized weak acid (pK1 3.0 to 7.5) such as phenobarbital subject to passive reabsorption.

Waddell and Butler (89) first demonstrated the effect of urine flow and urine pH on phenobarbital renal clearance in an anesthetized dog model in which diuresis was induced. Kapetanovic et al. (71) studied three epileptic patients receiving prolonged phenobarbital therapy. Twenty-four-hour serial urine samples were collected (n = 26). These investigators found a direct linear correlation between urine flow and urinary excretion of unchanged phenobarbital (r = .913) over a fourfold range of urine flow. In a group of 20 epileptic patients, Lous (29) demonstrated the same linear correlation between urine flow and phenobarbital renal clearance but also observed that the phenobarbital renal clearance was independent of phenobarbital concentration in the therapeutic range. The dependence of phenobarbital renal clearance on urine flow and urine pH has provided the basis for the use of urine alkalization and diuresis in patients who have had a phenobarbital overdose (89,90).


Healthy Subjects.

The elimination t½ of phenobarbital has been determined in numerous studies and ranges from 75 to 126 hours in healthy subjects and in patients receiving monotherapy (1, 2, 3, 4,5,14,29,91). Total plasma clearance ranges from 2.1 to 4.9 mL/hr/kg (1,2,14,91).

Comedicated Epileptic Patients.

Because phenobarbital is eliminated by multiple pathways (CYP450, N-glucosidation, and renal elimination of unchanged drug), the effect of enzyme inducers should be minimal. In a study of three patients receiving concurrent carbamazepine, the t½ of phenobarbital was 110, 122, and 128 hours, compared with 77, 83, and 98 hours in another three patients receiving concurrent phenytoin. However, neither was significantly different from the t½ in six normal subjects (75 to 126 hours) (1). Valproate significantly decreases the plasma clearance of phenobarbital by inhibiting the formation of both PNG and PBOH (71,88,92). A population study in South African children reported mean phenobarbital clearances of 7.6, 5.0, and 6.8 mL/hr/kg in children receiving phenobarbital monotherapy, polytherapy with valproate, or polytherapy with carbamazepine or phenytoin, respectively (93).


Newborns receiving phenobarbital for the treatment of neonatal seizures have a t½ ranging from 43 to 217 hours (7,21,24,25,94, 95, 96) and a total clearance of 2.7 to 10.7 mL/hr/kg (21,94). Phenobarbital clearance in asphyxia in neonates (22) was significantly lower (4.1 mL/hr/kg) compared with nonasphyxiated neonates (8.7 mL/h/kg). In children receiving phenobarbital, the t½ ranged from 37 to 198 hours (7,25). In a study of nine pediatric patients, the clearance in the children, ages 8 months to 4 years, was significantly greater than that reported in adults and ranged from 5.3 to 14.1 mL/hr/kg (97).

Elderly Patients.

There is no information of the absorption, volume of distribution, or t½ of phenobarbital in elderly patients. Total clearance of phenobarbital was significantly reduced in a group of patients >40 years old (2.5 ml/hr/kg) compared with patients 15 to 40 years old (4.9 mL/hr/kg) (98).

Comorbid Conditions.

The t½ of phenobarbital was prolonged in a group of patients with liver cirrhosis (130±15 hours) compared with a group of healthy subjects (86±3


hours). In patients with acute hepatitis, the t½ tended to be longer (60 to 127 hours) but was not significantly different from that of controls (99).


Large population studies have identified age and cotherapy as the primary determinants of the serum concentration:dose ratio. In an evaluation of data obtained from 536 patients receiving phenobarbital monotherapy, Duran et al. (100) found a decrease of the concentration:dose ratio with increasing age from <3 years, 3 to 6 years, 7 to 9 years, 10 to 14 years, and 15 to 18 years, with corresponding increasing concentration to dose ratios of 3.87±0.15, 4.65±0.16, 6.13±0.29, 7.54±0.73, and 10±1.1, respectively. A similar relationship with age was found in studies by Eadie et al. (98) in a group of 121 patients and by Suzuki et al. in a group of 438 patients (101).

Suzuki et al. (101) found that the concentration:dose ratio was higher in patients receiving phenobarbital in combination with other drugs mainly including phenytoin, valproate, and carbamazepine. Similar results were noted by Yukawa et al. (102) in a population study of 349 pediatric and adult patients with epilepsy in whom polytherapy with valproate or carbamazepine increased the concentration:dose ratio. Botha et al. reported that polytherapy with valproate, phenytoin, or carbamazepine resulted in an increase in the concentration:dose ratio (93).

Eadie et al. (98) demonstrated that sex was a determinant of the concentration:dose ratio only for children <5 years of age; boys required a higher dose (mg/kg) than girls. Sex was not found to be a factor in the other studies (100,101).


The recommended therapeutic range for phenobarbital is 10 to 40 µg/mL; however, neither the concentration effect nor the concentration-toxicity relationship is well defined (103). The range is based on studies largely in adults (104, 105, 106). Schmidt et al. (106) showed that the therapeutic range varied according to seizure type. Significantly higher phenobarbital plasma concentrations were necessary to control simple or partial complex seizures with or without secondarily generalized seizures (38±6 µg/mL.) than generalized tonic-clonic seizures only (18±10 µg/mL). Tolerability to the sedative adverse effects of phenobarbital alters the relationship of concentration with toxicity. Initial doses at very low phenobarbital concentration can cause excessive sedation and ataxia; however, over several weeks, tolerability to much higher phenobarbital concentrations can occur (107).


  1. Wilensky AJ, Friel PN, Levy RH, et al. Kinetics of phenobarbital in normal subjects and epileptic patients. Eur J Clin Pharmacol1982;23:87-92.
  2. Nelson E, Powell JR, Conrad K, et al. Phenobarbital pharmacokinetics and bioavailability in adults. J Clin Pharmacol1982; 22:141-148.
  3. Viswanathan CT, Booker HE, Welling PG. Bioavailability of oral and intramuscular phenobarbital. J Clin Pharmacol1978; 18:100-105.
  4. Nishihara K, Katsuyoski U, Saitoh Y, et al. Estimation of plasma unbound phenobarbital concentration by using mixed saliva. Epilepsia1979;20:37-45.
  5. Barzaghi N, Gatti G, Manni R, et al. Comparative pharmacokinetics and pharmacodynamics of eterobarbital and phenobarbital in normal volunteers. Eur J Drug Metabol Pharmacokinet1991;16:81-87.
  6. Graves NM, Homes GB, Kriel RL, et al. Relative bioavailability of rectally administered phenobarbital sodium parenteral solution. DICP1989;23:565-568.
  7. Jalling B. Plasma and cerebrospinal fluid concentrations of phenobarbital in infants given single doses. Dev Med Child Neurol1974;11:781-793.
  8. Syed GB, Sharma DB, Raina RK. Pharmacokinetics of phenobarbitone in protein energy malnutrition. Dev Pharmacol Ther1986;9:317-322.
  9. Berg JM, Berlinger WG, Goldberg MJ, et al. Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med1982;307:642-644.
  10. Goldberg MJ, Berlinger WG. Treatment of phenobarbital overdose with activated charcoal. JAMA1982;247:2400-2401.
  11. Neuvonen PJ, Elonen E. Effect of activated charcoal on absorption and elimination of phenobarbitone, carbamazepine and phenylbutazone in man. Eur J Clin Pharmacol1980;17:51-57.
  12. Veerman M, Espejo MG, Christopher MA, et al. Use of activated charcoal to reduce elevated serum phenobarbital concentration in a neonate. Clin Toxicol1991;29:53-58.
  13. Berg MJ, Rose JQ, Wurster DE, et al. Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital. Ther Drug Monit1987;9:41-47.
  14. Browne TR, Evans JE, Szabo GK, et al. Studies with stable isotopes. II. Phenobarbital pharmacokinetics during monotherapy. J Clin Pharmacol1985;25:51-58.
  15. Berg JM, Rose JQ, Wurster DE, et al. Effect of charcoal and sorbitol-charcoal suspension on the elimination of intravenous phenobarbital. Ther Drug Monit1987;9:41-47.
  16. Svensmark O, Buchthal F. Accumulation of phenobarbital in man. Epilepsia1963;4:199-206.
  17. Painter MJ, Pippenger C, et al. Phenobarbital and diphenylhydantoin levels in neonates with seizures. Pediatrics1978;92: 315-319.
  18. Painter MJ, Pippenger C, et al. Phenobarbital and phenytoin blood levels in neonates. Pediatrics1977;92:315-319.
  19. Painter MJ, Pippenger C. Phenobarbital and phenytoin in neonatal seizures: metabolism and tissue distribution. Neurology1981;31:1107-1112.
  20. Jalling B. Plasma concentrations of phenobarbital in the treatment of seizures in the newborn. Acta Paediatr Scand1975;64: 514-524.
  21. Fischer JH, Lockman LA, Zaske D, et al. Phenobarbital maintenance doses requirements in treating neonatal seizures. Neurology1981;31:1042-1044.
  22. Gal P, Erkan NV, et al. The influence of asphyxia on phenobarbital dosing requirements in neonates. Dev Pharmacol Ther1984;7:145-152.



  1. Lockman LA, Kriel RL, Zaske D, et al. Phenobarbital dosage for control of neonatal seizures. Neurology1979;29:1445-1449.
  2. Grasela THJ, Donn SM. Neonatal population pharmacokinetics of phenobarbital derived from routine clinical data. Dev Pharmacol Ther1985;8:374-383.
  3. Heimann G, Gladtke E. Pharmacokinetics of phenobarbital in childhood. Eur J Clin Pharmacol1977;12:305-310.
  4. Brachet-Liermain A, Gouteres F, Aicardia J. Absorption of phenobarbital after the intramuscular administration of single doses in infants. J Pediatr1975;87:624-626.
  5. Dodson WE, Rust RS. Phenobarbital: absorption, distribution and excretion. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic drugs,4th ed. New York: Raven Press, 1994.
  6. Wilkes L, Danziger LH, Rodvold KA. Phenobarbital pharmacokinetics in obesity: a case report. Clin Pharmacokinet1992; 22:481-484.
  7. Lous P. Blood serum and cerebrospinal fluid levels and renal clearances of phenemal in treated epileptics. Acta Pharmacol Toxicol1954;10:166-177.
  8. Ehrnebo M, Agurell S, Jalling B, et al. Age differences in drug binding by plasma proteins: studies on human foetuses, neonates and adults. Eur J Clin Pharmacol1971;3:189-193.
  9. Goldbaum LR, Smith PK. The interaction of barbituates with serum albumin and its possible relation to their disposition and pharmacological actions. J Pharmacol Exp Ther1954;111: 197-209.
  10. Tokugawa K, Ueda K, Fujito H, et al. Correlation between the saliva and free serum concentration of phenobarbital in epileptic children. Eur J Pediatr1986;145:401-402.
  11. Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants: age-related differences and therapeutic implications. Clin Pharmacokinet1980;5:485-527.
  12. Veering BT, Burm AG, Souveijn JH, et al. The effect of age on serum concentrations of albumin and alpha 1-acid glycoprotein. Br J Clin Pharmacol1990;29:201-206.
  13. Schmidt D, Kupferberg H. Diphenylhydantoin, phenobarbital, and primidone in saliva, plasma, and cerebrospinal fluid. Epilepsia1975;16:735-741.
  14. Engasser JM, Sarahan F, Falcoz C, et al. Distribution, metabolism, and elimination of phenobarbital in rats: physiologically based pharmacokinetic model. J Pharm Sci1981;70: 1233-1238.
  15. Mayer S, Maickel RP, Brodie BB. Kinetics of penetration of drugs and other foreign compounds in cerebrospinal fluid and brain. J Pharmacol Exp Ther1959;127:205.
  16. Ramsay RE, Hammond EJ, Perchalski RJ, et al. Brain uptake of phenytoin, phenobarbital and diazepam. Arch Neurol1979;36: 535-539.
  17. Simon RP, Copeland JR, Benowitz NL, et al. Brain phenobarbital uptake during prolonged status epilepticus. J Cereb Blood Flow Metab1987;7:783-788.
  18. Harvey CD, Sherwin AL, Van Der Kleijn E. Distribution of anticonvulsant drugs in gray and white matter of human brain. Can J Neurol Sci1977;4:89-92.
  19. Houghton GW, Richens A, Toseland PA, et al. Brain concentrations of phenytoin, phenobarbital and primidone in epileptic patients. Eur J Clin Pharmacol1975;9:73-78.
  20. Sherwin AL, Eisen AA, Sagolowski CD. Anticonvulsant drugs in human epileptogenic brain. Arch Neurol1973;29:73.
  21. Vajda F, Williams FM, Davidson S, et al. Human brain, cerebrospinal fluid, and plasma concentrations of diphenylhydantoin and phenobarbital. Clin Pharmacol Ther1974;15: 597-603.
  22. Onishi S, Ohki Y, Nishimura Y, et al. Distribution of phenobarbital in serum, brain and other organs from pediatric patients. Dev Pharmacol Ther1984;7:153-159.
  23. Rambeck B, Schnabel R, May T, et al. Postmortem concentrations of phenobarbital, carbamazepine, and its metabolite carbamazepine-10,11-epoxide in different regions of the brain and in serum: analysis of autoptic specimens from 51 epileptic patients. Ther Drug Monit1993;15:91-98.
  24. Cook C, Amerson E, Poole W, et al. Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin Pharmacol Ther1975;18:742-747.
  25. Horning MG, Brown L, Nowlin J, et al. Use of saliva for therapeutic drug monitoring. Clin Chem1977;23:157-164.
  26. Troupin AS, Friel PN. Anticonvulsant level in saliva, serum and cerebrospinal fluid. Epilepsia1975;16:223-227.
  27. Goldsmith RF, Ouvrier RA. Salivary anticonvulsant levels in children: a comparison of methods. Ther Drug Monit1981;3: 151-157.
  28. Friedman IM, Litt IF, et al. Saliva phenobarbital and phenytoin concentrations in epileptic adolescents. J Pediatr1981;98: 645-647.
  29. McAuliffe JJ, Sherwin AL, Leppik IE, et al. Salivary levels of anticonvulsants: a practical approach to drug monitoring. Neurology1977;27:409-413.
  30. Plomann L, Persson BH. On the transfer of barbituates to the human fetus and their accumulation in some of its vital organs. J Obstet Gynecol1957;64:706-711.
  31. Persson BH. Studies on the accumulation of certain barbituates in the brain of the human fetus. Acta Obstet Gynecol1960;39: 88-99.
  32. Nau H, Kuhnz W, Egger HJ, et al. Anticonvulsants during pregnancy and lactation: transplacental, maternal and neonatal pharmacokinetics. Clin Pharmacokinet1982;7:508-543.
  33. Boreus LO, Jalling B, Wallin A. Plasma concentrations of phenobarbital in mother and child after combined prenatal and postnatal administration for prophylaxis of hyperbilirubinemia. J Pediatr1978;93:695-698.
  34. Bossi L, Battino D, Caccamo ML, et al. Pharmacokinetics and clinical effects of antiepileptic drugs in newborns of chronically treated epileptic mothers. In: Janz D, Dam M, Richens A, et al., eds. Epilepsy, pregnancy, and the child.New York: Raven Press; 1982:373-381.
  35. Jalling B, Boreus LO, Kallberg N, et al. Disappearance from the newborn of circulating prenatally administered phenobarbital. Eur J Clin Pharmacol1973;6:234-238.
  36. Kuhnz W, Koch S, Helge H, et al. Primidone and phenobarbital during lactation period in epileptic women: total and free drug serum levels in the nursed infants and their effect on neonatal behavior. Dev Pharmacol Ther1988;11:147-154.
  37. Melchior JC, Svensmark O, Trolle D. Placental transfer of phenobarbitone in epileptic women, and elimination in newborns. Lancet1967;11:860-861.
  38. Nau H, Rating D, Hauser I, et al. Placental transfer and pharmacokinetics of primidone and its metabolites, phenobarbital, PEMA and hydroxyphenobarbital in neonates and infants of epileptic mothers. Eur J Clin Pharmacol1980;18:18-42.
  39. Rating D, Nau H, Kuhnz W, et al. Antiepileptika in der neugeborenenperiode. Monatsschr Kinderheilkd1983;131:6-12.
  40. Shankaran S, Cepeda E, Ilagan N, et al. Pharmacokinetic basis for antenatal dosing of phenobarbital for the prevention of neonatal intracerebral hemorrhage. Dev Pharmacol Ther1986; 9:171-177.
  41. De Carolis MP, Romagnoli C, Frezza S, et al. Placental transfer of phenobarbital: What is New? Dev Pharmacol Ther1992;19: 19-26.
  42. Kaneko S, Suzuki K, Sato T, et al. The problems of antiepileptic medication in the neonatal periods: is breastfeeding advisable? In: Janz D, Dam M, Richens A, et al., eds.Epilepsy, pregnancy, and the child.New York: Raven Press, 1982:343-348.
  43. Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Saf2000;22:425-440.



  1. American Academy of Pediatrics Committee on Drugs. The transfer of drugs and other chemicals into human milk. Pediatrics1994;93:137-150.
  2. Butler TC. The metabolic hydroxylation of phenobarbital. J Pharmacol Exp Ther1956;116:326-336.
  3. Curry AS. Curry AS. A note on a urinary metabolite of phenobarbitone. J Pharm Pharmacol1955;7:1072-1073.
  4. Kadar D, Tang BK, Conn AW. The fate of phenobarbitone in children in hypothermia and at normal body temperature. Can Anaesth Soc J1982;29:16-23.
  5. Whyte MP, Dekaban AS. Metabolic fate of phenobarbital: a quantitative study of p-hydroxyphenobarbital elimination in man. Drug Metab Dispos1977;5:63-70.
  6. Kapetanovic IM, Kupferberg HJ, Porter RJ, et al. Mechanism of valproate/phenobarbital interaction in epileptic patients. Clin Pharmacol Ther1981;29:480-486.
  7. Raven-Jonsen A, Lundin M, Secher O. Excretion of phenobarbitone in urine after intake of large doses. Acta Pharmacol Toxicol (Kbh)1968;27:193-201.
  8. Tang BK, Kalow W, Grey AA. Metabolic fate of phenobarbital in man: N-glucoside formation. Drug Metab Dispos1979;7: 315-318.
  9. Tang BK, Yilmaz B, Kalow W. Determination of phenobarbital, p-hydroxyphenobarbital and phenobarbital-N-glucoside in urine by gas chromatography chemical ionization mass spectrometry. Biomed Mass Spectrom1983;11:462-465.
  10. Boreus LO, Jalling B, Kallberg N. Phenobarbital metabolism in adults and in newborn infants. Acta Paediatr Scand1978;67: 193-200.
  11. Bernus I, Dickinson RG, Hooper WD, et al. Urinary excretion of phenobarbitone and its metabolites in chronically treated patients. Eur J Clin Pharmacol1994;46:473-475.
  12. Danhof M, Levy G. Kinetics of drug action in disease states. I. Effect of infusion rate on phenobarbital concentrations in serum, brain and cerebrospinal fluid of normal rats at onset of loss of righting reflex. J Pharmacol Exp Ther1984;229:44-50.
  13. Bhargava VO, Soine WH, Garrettson LK. High performance liquid chromatographic analysis of 1-(D-glucopyranosyl)-phenobarbital in urine. J Chromatogr1985;343:219-223.
  14. Bhargava VO, Garrettson LK. Development of phenobarbital glucosidation in the human neonate. Dev Pharmacol Ther1988; 11:8-13.
  15. Vest FB, Soine WH, Westkaemper RB, et al. Stability of phenobarbital N-glucoside: identification of hydrolysis products and kinetics of decomposition. Pharm Res1989;6:458-465.
  16. Harvey DU, Glazner L, Stratton G, et al. Detection of a 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-metabolite of phenobarbital and mephobarbital in rat, guinea pig, and human. Res Commun Chem Pathol Pharmacol1972;3:557-565.
  17. Horning EC, Horning MG. Metabolic profiles: gas phase methods for analysis of metabolites. Clin Chem1971;17:802-809.
  18. Treston AM, Philippides A, Jacobsen NW, et al. Identification and synthesis of O-methylcatechol metabolites of phenobarbital and some n-alkyl derivatives. J Pharm Sci1987;76:496-501.
  19. Hargraves JA, Howald WN, Racha JK, et al. Identification of enzymes responsible for the metabolism of phenobarbital. Int Soc Stud Xenobiot Proc1996;10:259(abst).
  20. Mamiya K, Hadama A, Yukawa E, et al. CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. Eur J Clin Pharmacol2000;55:821-825.
  21. Tang BK, Kalow W, Grey AA. Amobarbital metabolism in man: N-glucoside formation. Res Commun Chem Pathol Pharmacol1978;21:45-53.
  22. Remmer H, Siegert M. Kumulation and elimination von phenobarbital. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol1962;243:479-494.
  23. Patel IH, Levy RH, Cutler RE. Phenobarbital-valproic acid interaction. Clin Pharmacol Ther1980;27:515-521.
  24. Waddell WJ, Butler TC. Distribution and excretion of phenobarbital. J Clin Invest1957;36:1217-1226.
  25. Gary NE, Tresznewsky O. Barbiturates and a potpourri of other sedatives, hypnotics and tranquilizers. Heart Lung1983;12: 122-127.
  26. Pullar T, Kumar S, Chrystyn H, et al. The prediction of steady-state phenobarbitone concentrations (following low-dose phenobarbitone) to refine its use as an indicator of compliance. Br J Clin Pharmacol1991;32:329-333.
  27. Bernus I, Dickinson G, Hooper WD, et al. Inhibition of phenobarbitone N-glucosidation by valproate. Br J Clin Pharmacol1994;38:411-416.
  28. Botha JH, Gray AL, Miller R. Determination of phenobarbitone population clearance values for South African children. Eur J Clin Pharmacol1995;48:381-383.
  29. Donn SM, Grasela THJ, Goldstein GW. Safety of a higher loading dose of phenobarbital in the term newborn. Pediatrics1985;75:1061-1064.
  30. Pitlick W, Painter M, Pippenger C. Phenobarbital pharmacokinetics in neonates. Clin Pharmacol Ther1978;23:346-350.
  31. Taburet AM, Chamouard C, Aymard P, et al. Phenobarbital protein binding in neonates. Dev Pharmacol Ther1982;4[Suppl 1]:129-134.
  32. Davis AG, Mutchie KD, Thompson JA, et al. Once-daily dosing with phenobarbital in children with seizure disorders. Pediatrics1981;68:824-827.
  33. Eadie MJ, Lander CM, Hooper W, et al. Factors influencing plasma phenobarbitone levels in epileptic patients. Br J Clin Pharmacol1977;4:541-547.
  34. Alvin J, McHorse T, Hoyumpa A, et al. The effect of liver disease in man on the disposition of phenobarbital. J Pharmacol Exp Ther1975;192:224-235.
  35. Duran JA, Sanchez A, Serrano MI, et al. Phenobarbital plasma/level dose ratio in monotherapy: influence of age, sex and dose. Methods Find Exp Clin Pharmacol1988;10:337-340.
  36. Suzuki K, Cox S, Hayes J, et al. Phenobarbital doses necessary to achieve “therapeutic” concentrations in children. Dev Pharmacol Ther1991;17:79-87.
  37. Yukawa E, To H, Ohdo S, et al. Detection of drug-drug interaction on population-based phenobarbitone clearance using nonlinear mixed-effects modeling. Eur J Clin Pharmacol1998; 54:69-74.
  38. Theodore W. Rational use of antiepileptic drug levels. Pharmacol Ther1992;54:297-305.
  39. Buchthal F, Svensmark O, Simonsen H. Relation of EEG and seizures to phenobarbital in serum. Arch Neurol1968;19: 567-672.
  40. Feely M, O'Callagan M, Duggan B, et al. Phenobarbitone in previously untreated epilepsy. J Neurol Neurosurg Psychiatry1980;43:365-368.
  41. Schmidt D, Einicke I, Haenel F. The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital and carbamazepine. Arch Neurol1986;43:263-265.
  42. Cramer JA, Mattson RH. Phenobarbital: Toxicity. In: Levy RH, Mattson RH, Meldrum BS, ed. Antiepileptic drugs,4th ed. New York: Raven Press, 1994:409-420.
  43. Garrettson LK, Dayton PG. Disappearance of phenobarbital and diphenylhydantoin from serum of children. Clin Pharmacol Ther1970;11:674-679.