Br. J. clin. Pharmac.

(1978), 5, 313-318

PHARMACOKINETICS OF VALPROIC ACID AFTER ORAL AND INTRAVENOUS ADMINISTRATION

E. PERUCCA, G. GATTI, G.M. FRIGO & A. CREMA
Institute of Medical Pharmacology, University of Pavia, Pavia, Italy

1 The kinetics of sodium valproate (di-n-propyl-acetate, Depakine@1) have been studied in six healthy volunteers after administration of single oral and intravenous doses (800 mg). 2 Kinetic parameters were similar for both routes of administration. In all subjects absorption was rapid and complete. Half-lives ranged from 11-15 h. Apparent volumes of distribution were relatively low (0.147 + 0.004 1/kg) and showed little variation amongst individuals. 3 The factors responsible for the poor correlation between dosage and serum levels during chronic treatment and therapeutic implications are discussed.

Introduction Since its anticonvulsant properties were first described in 1963 by Meunier, Carraz, Meunier, Eymard & Aimard sodium valproate (sodium di-n-propylacetate) has been increasingly used for the treatment of epilepsy (Simon & Penry, 1975; Pinder, Brogden, Speight & Avery, 1977). In addition to a large number of uncontrolled studies two double-blind placebo controlled trials have established its efficacy against both major and minor epileptic seizures (Meinardi, 1971; Richens & Ahmad, 1975). Although serum valproic acid levels are frequently monitored during chronic therapy and a tentative therapeutic range has been suggested (Schobben, Van der Kleijn & Gabreels, 1975) the kinetics of the drug have been little investigated and intravenous studies in man are lacking (Schobben et al., 1975; Meijer & Meinardi, 1976; Richens, Scoular, Ahmad & Jordan, 1976). In the present study we have administered single oral and intravenous doses of sodium valproate to healthy volunteers in order to collect information on the absorption and elimination kinetics and to assess the absolute biological availability of the drug.
Methods

Experimental design and analyticalprocedures

Six healthy male volunteers, aged between 22-38 years, gave their informed consent to participate in the trial. None had taken any drug in the month preceding the study. Each subject received, at an interval of 10 days, single oral and intravenous doses of sodium valproate (800 mg). The oral preparation was the

commercially available 200 mg tablets (Depakine, Sigma-Tau, Italy) while for the intravenous study we used vials containing 400 mg of lyophylized sodium valproate, dissolved in 4 ml distilled water immediately before use. Sequence of treatments was randomized. The injection was given slowly over a period of 5 min. On both occasions the drug was administered at 08.00 h after an overnight fast. A small cup of weak tea was permitted at the time of administration. No other fluid or food was permitted during the next 3 h. No side effects were observed. Blood samples (10 ml) were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 11, 14, 24, 28, 32, 36 and 48 hpost administration. In three subjects additional samples were taken at 0.25, 0.75 and 1.5 h after the intravenous dose. Serum specimens were kept frozen at -20C and analyzed within 1 week. Serum valproic acid concentrations were determined in duplicate using 0.5 ml samples by gaschromatography according to Schultz & Toseland (1977). The gas-chromatograph was a Perkin Elmer F33 fitted with dual FID. The column was a 2 m glass column, 3 mm i.d., filled with 5% WG 11 on Gas Chrom Q 80-100 mesh. Temperature of the column was 1700C, temperature of the injector and detector 225C. Gas flows were 40 ml/min (nitrogen) and 20 p.s.i. (air and hydrogen).

Compartmental analysis
Data were analyzed according to one-compartment open model, despite the occurrence of a short distributive phase in four subjects after intravenous administration. After 1-2 h following the injection and 3-6 h following the oral administration the

314

E. PERUCCA, G. GATTI, G.M. FRIGO & A. CREMA

decline of the log-valproic acid concentration with respect to time appeared linear. The least square regression line was calculated for each subject and extrapolated back to find the concentration at zero time (C0). The extrapolated apparent volume of distribution ( Vd extrap) was calculated from intravenous data as Dose/C0 and from oral data as F * Dose/C0 (where F is the fraction absorbed). Areas under the concentration curves were estimated by the trapezoidal rule from 0 to 48 h and from 48 h to oo by the relationship C48/ Kel (C48 being the concentration at 48 h and Kel the elimination rate constant). The total serum clearance (Cl) was calculated from the intravenous data according to the formula (Wagner, Northam, Alway & Carpenter, 1965):

Cl = Dose/AUCo,. The apparent volume of

distribution Vd area, a term which is independent of the model used (Gibaldi, 1969), was calculated from intravenous data as Dose/(AUCOo Kei) and from oral data as (F * Dose)/(AUC00 * Kel) (Wagner, Northam, Alway & Carpenter, 1965). In three subjects more frequent sampling allowed analysis of the intravenous curves according to a twocompartment open model. The P slope (terminal slope) was obtained by linear regression from the last part of the curve. The a slope (rapid slope) was obtained by subtracting the f curve, extrapolated back to zero time, from the serum concentrations shortly after administration. Bi-compartmental analysis was performed as described by Wagner (1971).
Results

Table 1 Mean + s.d. serum valproic acid concentrations after single oral and intravenous doses

(800 mg)
Time

Intravenous

Oral

(h)
0 0.5
1

(9ig/mi)
0.0 0.0 98.6 10.9 87.3 11.5 79.0+10.0 71.8 12.6 64.8 9.5 55.5 + 5.8 48.7 + 6.4 43.9 + 3.8 36.4 + 2.6 20.7 + 2.9 16.7+ 2.4 13.4+ 3.0 10.8 3.2 6.0 + 1.8

(9ig/m/)
0.0+ 0.0 57.6 19.7 66.8 13.7 77.0 12.6 74.614.0 69.2 11.3
56.3 +10.0 46.0 7.4 37.0+ 7.3 20.0+ 2.7 16.5+ 4.6 13.4+ 3.1 10.7 3.8 5.9+ 1.4

2 3 4 6 8 11 14 24 28 32 36 48

62.511.1

Serum valproic acid concentrations at different times after single oral and intravenous doses (800 mg) are shown in Figure 1 while mean values and standard deviations are summarized in Table 1. After intravenous administration the decline of log-valproic acid concentrations versus time appeared biexponential in four subjects, although the distributive phase was short and almost completed after 2-4 h. In two subjects (BN and TM) a biexponential decay could not be clearly distinguished. Kinetic parameters calculated according to one-compartment open model are shown in Table 2. Half-lives, apparent volumes of distribution and areas under the concentration curves (AUC) showed very little variation amongst individuals. Volumes of distribution showed even less interindividual variation when calculated per unit of body weight. Correlation between Vd area and body weight was highly significant when tested statistically (r=0.964, P 0.005). Vd extrap was similar to Vd area.

Table 2 Kinetic parameters calculated from serum valproic acid concentrations after single intravenous doses (800 mg)

Subject
BN FG PA

Weight

(kg)
65 6*1 78 75 69 60 68 7

(9ig/m/)
78.7 85.3 68.1
71.1

CO

(h-1)
0.0647 0.0530 0.0458 0.0454 0.0576 0.0631 0.0549 0.0083

Kel

Ty%

(h)

Vd extrap Vd area Vd area/kg AUCO048 AUCO-. (I) ) (I/kg) (mg lI h) (mg /-1 h)

(I/h)
0.61 0.47 0.50 0.49 0.61 0.57 0.54 0.06

C/

SM TM VB Mean s.d.

74.3 87.5 77.5 7.8

10.7 13.1 15.1 15.3 12.0 11.0 12.8 1.6

10.2 9.4 11.7 11.2

10.8 9.1 10.4

1.0

9.6 8.9 11.0 10.8 10.6 9.0 10.0 0.9

0.147 0.145 0.141 0.144 0.153 0.150 0.147 0.004

1237 1574 1429 1447 1213 1334 1372 137

1293 1704 1584 1634 1312 1404 1488 175

CO, Extrapolated zero time intercept of the terminal slope; K., and Tj, rate constant and half-life of the terminal slope respectively; Vdextrap= Dose(CO;Vd area= Dose/(K., * AUCO_-J); AUC, area underthe serum concentration curves; Cl, total serum clearance.

PHAR MACO KI N ETI CS OF VALPRO I C ACI D

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Figure 1

Serum valproic acid concentration curves following single oral

(800 mg) in six subjects.

(@)

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Analysis according to a two-compartment open model was also performed in three subjects in whom the biexponential decay could be better distinguished because of additional early samples. The corresponding calculated kinetic parameters are shown in Table 3. After oral doses serum valproic acid levels rose rapidly within 1-3 h to values similar to those obtained with intravenous administration. The kinetic parameters calculated from oral data were also similar to those found after parenteral administration (Table 4). The absolute biological availability assessed by the ratio between total AUCs after oral and intravenous

administration was virtually complete in all individuals (Table 4).

Discussion
The comparison of serum valproic acid concentration curves following different routes of administration shows some interesting features. After intravenous administration the initial distributive phase was rapid and after 1-2 h serum levels declined with a monoexponential decay. Therefore the data could be adequately described in terms of a one-compartment

316

E. PERUCCA, G. GATTI, G.M. FRIGO & A. CREMA

open model. The same model has been used previously to describe valproic acid elimination kinetics in dogs (Schobben & Van der Kleijn, 1974) and in man after oral subchronic treatment (Schobben et al., 1975). However, analysis of data according to a twocompartment open model was possible in three subjects. The half-lives of the a slope averaged 0.5 h as opposed to 12 h for the P slope. The fact that distribution is rapid does not necessarily imply that it is unimportant, especially when the drug is administered intravenously and a prompt effect is required. Following oral doses serum valproic acid levels rose rapidly within 1-3 h to values similar to those found at corresponding times after intravenous administration. A similar time course of serum concentrations has been observed by using different brand tablets in healthy volunteers, while an even faster absorption rate has been described in epileptic patients (Richens et al., 1976). It is of interest that a single 800 mg dose produced serum levels considered optimal for seizure control (Schobben et al., 1975). Absorption of sodium valproate has been assumed on theoretical grounds to be complete (Schobben et

al., 1975; Richens et al., 1976) but this assumption has never been confirmed by intravenous studies. According to our results the biological availability of sodium valproate is 100%. Paradoxically one subject (VB) showed a bioavailability higher than 100% (117%). In this subject the butterfly infusion set had to be changed due to vein rupture during the intravenous administration and a small fraction of the dose was probably lost. The calculated kinetic parameters appeared independent of the route of administration. In all subjects half-lives were similar and within the range quoted by Meijer & Meinardi (1976). Slightly shorter half-lives have been described previously in healthy volunteers (Richens et al., 1976) and non-epileptic patients (Loiseau, Brachet & Henry, 1975), while values of 4-8 h have been observed in patients chronically treated with other antiepileptic drugs (Richens et al., 1976). Volumes of distribution also showed little variation amongst individuals and were similar to those previously found in healthy subjects (Richens et al., 1976) while higher figures have been described in patients with adult and

Table 3 Kinetic parameters calculated from serum valproic acid concentrations after single intravenous doses (800 mg) according to a two-compartment open model

Subject FG SM VB

(pg/m/)
51.3 39.3 61.6

(h-I)
1.15 0.88 3.26

T+a (h)
0.60 0.78 0.21

T1
(

(pg/m/)
85.3 71.1 87.5

(h-1)
0.0530 0.0454 0.0631

K12 WI (h-1)
0.383 0.275 1.278

(h-1)
0.738 0.582 1.939

K21

Kel Wh-I)
0.082 0.068 0.106

13.08 15.26 10.98

A and B, Extrapolated zero-time intercepts of the a and jS slopes respectively; a and p rate constants of the a (rapid) and / (terminal) slopes respectively; T a and T, /, half-lives of the a and /5 slopes respectively; Kl2 and K2, transfer rate constants respectively from the central to the peripheral compartment and vice versa; Kel, elimination rate constant from the central compartment.

Table 4

(800 mg) and absolute biological availability

Subject
Peak serum Time of peak level

Kinetic parameters calculated from serum valproic acid concentrations after single oral doses

4tg/ml)
BN

(h)
2 0.5 2 2 0.5 4 1.8 1.3

Kel (h-')
0.0718 0.0520 0.0530 0.0463 0.0484

Tj

Vd extrap Vd area

AUC048

AUC0,.
1273 1567 1442 1585 1359 1645 1478 145

(h)
9.6 13.3 13.1 15.0 14.3 11.1 12.7 2.0

(I) (I)
8.6 10.4 10.6 10.2 12.6 8.8 10.2 1.4
8.6 8.9 9.5 10.6 12.5 9.1 9.9 1.5

(mg L' h) (mg f1- h)

1226 1444 1334 1430 1212 1552 1366 133

AUC ora A UC ,vLO

FG PA SM TM VB Mean s.d.

76.3 87.0 91.4 88.1 59.3 89.2 81.9 12.2

0.0624 0.0556 0.0097

0.98 0.91 0.91 0.97 1.03 1.17 1.00 0.10

Vd extrap = F Dose/CO (where F is the fraction absorbed) Vd area= F * Dose/(AUC 0-.,Ke.). Other symbols as in legend of Table 2.

PHARMACOKINETICS OF VALPROIC ACID

317

childhood epilepsy (Schobben et al., 1975; Richens et al., 1976). The low volume of distribution of sodium valproate, as compared to most antiepileptic drugs, may have important clinical implications. It has been suggested that the distribution of the drug is mainly restricted to the blood stream and rapidly exchangeable body water. Therefore the concentration in the brain should be relatively low and the serum level required for therapeutic effect comparatively high (Schobben et al., 1975). This assumption correlates with the observation that 'therapeutic' levels of valproic acid are in molar terms much higher than the suggested therapeutic range of other antiepileptic drugs. The low volume of distribution of valproic acid is partially due to its high degree of plasma protein binding (Jordan, Shillingford & Steed, 1976). For a drug with such a low volume of distribution any change in the degree of plasma protein binding, due to disease or displacement by other drugs, may significantly alter the amount of drug in the tissues and correspondingly influence both therapeutic and toxic effects (Sj6qvist, Borga & Orme, 1976). A large variability of serum valproic acid levels has been described in patients receiving the same dose during chronic treatment (Haigh & Forsythe, 1975; Loiseau et al., 1975; Hassan, Laljee & Parsonage, 1976). Schobben et al. (1975) discussed the possibility of incomplete absorption but such explanation seems unlikely in the light of the present results. In our group of subjects serum levels and corresponding kinetic parameters showed little interindividual variation, in contrast with the findings of most of the above mentioned studies. Indeed a poor correlation between dosage and serum levels would not be expected for a
References
GIBALDI, M. (1969). Effect of mode of administration on drug distribution in a two-compartment open system. J. pharmn. Sci., 58, 327-33 1. HAIGH, D. & FORSYTHE, W.I. (1975). The treatment of childhood epilepsy with sodium valproate. Developm.

drug which according to our results shows complete bioavailability and little interindividual differences in volume of distribution and elimination rate. The reported variability in serum valproic acid levels during chronic therapy could be explained by: -the short half-life of valproic acid. Even if the drug is administered frequently, serum levels fluctuate widely during the day so that the time of sampling influences considerably the concentration values; the influence of concurrent administration of other antiepileptic drugs on the kinetics of sodium valproate. As mentioned above, both absorption rate and volume of distribution have been claimed to be higher in epileptic patients (Richens et al., 1976). Moreover it has been reported that sodium valproate is eliminated at a faster rate in epileptic patients as compared to normal volunteers (Richens et al., 1976) although other studies have failed to confirm these findings (Meinardi, 1976). Since in the present study serum concentrations comparable with those attained during chronic therapy declined with first-order kinetics it seems unlikely that dose dependent kinetics occur at the commonly prescribed dosage regimes and therefore this would not explain the observed variability in steady state levels.

The authors wish to thank Dr Alan Richens for kindly reading the manuscript. Sigma-Tau (Pomezia, Italy) is acknowledged for supplying the vials of lyophylized sodium valproate. This study was supported by a research grant from the Anna Villa Rusconi Foundation, Varese, Italy.

Med. Child Neurol., 17, 743-748.

HASSAN, M.N., LAUEE, H.C.K. & PARSONAGE, M.J.

MELER, J.W.A. & MEINARDI, H. (1976). Pharmacokinetic studies on sodium valproate. In Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy, ed. Legg, N.J., pp. 70-74. Tunbridge Wells: MCS Consultants. MEINARDI, H. (1971). Clinical trials of antiepileptic drugs.

(1976). Experience in the treatment of resistant cases of epilepsy with sodium valproate (Epilim). In Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy, ed. Legg, NJ., pp. 23-39. Tunbridge Wells: MCS Consultants. JORDAN, B.J., SHILLINGFORD, J.S. & STEED, K.P. (1976). Preliminary observations on the protein-binding and enzyme-inducing properties of sodium valproate (Epilim). In Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment ofepilepsy, ed. Legg, N.J., pp. 112-116. Tunbridge Wells: MCS Consultants. LOISEAU, P., BRACHET, A. & HENRY, P. (1975). Concentration of dipropylacetate in plasma. Epilepsia (Amst.), 16,609-615.

Psychiatr. Neurol. Neurochir., 74,435-483. MEINARDI, H. (1976). In Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy, ed. Legg, NJ., pp. 74. Tunbridge Wells: MCS Consultants.
MEUNIER, H., CARRAZ, G., MEUNIER, Y., EYMARD, P. &

AIMARD, M. (1963). Propriet;s pharmacodinamiques de l'acide n-dipropylac6tique. Therapie, 18, 435-438.

PINDER, R.M., BROGDEN, R.N., SPEIGHT, T.M. & AVERY,

G.S. (1977). Sodium valproate: a review of its pharmacological properties and therapeutic efficacy in epilepsy. Drugs, 13, 81-123. RICHENS, A. & AHMAD, S. (1975). Controlled trial of sodium valproate in severe epilepsy. Br. med. J., 4, 255-256.
RICHENS, A., SCOULAR, I.T., AHMAD, S. & JORDAN, B.J.

318

E. PERUCCA, G. GATTI, G.M. FRIGO & A. CREMA

(1976). Pharmacokinetics and efficacy of Epilim in

patients receiving long-term therapy with other antiepileptic drugs. In Clinical and pharmacological aspects of sodium valproate (Epilim) in the treatment of epilepsy, ed. Legg, N.J., pp. 78-88. Tunbridge Wells: MCS Consultants. SCHOBBEN, F. & VAN DER KLEUN, E. (1974). Pharmacokinetics of distribution and elimination of di-npropylacetate in mouse and dog. Pharm. Weekblad., 109, 33-42.
SCHOBBEN, F., VAN DER KLEUN, E. & GABREELS, F.J.M.

SIMON, D. & PENRY, J.K. (1975). Sodium di-n-propylacetate (DPA) in the treatment of epilepsy. A review. Epilepsia (Amst.), 16, 549-573. SJ6QVIST, F., BORGA, 0. & ORME, M.L.E. (1976). Fundamentals of clinical pharmacology. In Drug treatment, ed. Avery, G.S., pp. 1-42. Sydney: Adis Press.
WAGNER, J.G., NORTHAM, J.I., ALWAY, C.D. &

(1975). Pharmacokinetics of di-n-propylacetate in epileptic patients. Eur. J. clin. Pharmac., 8, 97-105. SCHULTZ, F.U. & TOSELAND, P.A. (1977). Determination of the anticonvulsant drug sodium dipropylacetate in human plasma by gas chromatography. Ann. clin. Biochem. (in press).

CARPENTER, O.S. (1965). Blood levels of drugs at equilibrium state after multiple dosing. Nature, 207, 1301-1302. WAGNER, J.G. (1971). Biopharmaceutics and relevant pharmacokinetics. Hamilton, Illinois: Drug Intelligence Publications.

(Received April 12, 1977)

Note added in proof: After this article had been accepted, Klotz & Antonin (1977) reported the results of a study in which the absolute availability of sodium valproate was also determined in healthy volunteers. Despite differences in the experimental design, including the use of different type of brand tablets and bi-compartmental analysis, their data are in good agreement with those observed by us, although a higher interindividual variability was found. In a later study in which the same protocol was used
References
KLOTZ, U. & ANTONIN, K. H. (1977). Pharmacokinetics and bioavailability of sodium valproate. Clin. Pharmac. Ther., 21, 736-743.

we have investigated the disposition of sodium valproate in epileptic patients receiving chronic treatment with other antiepileptic drugs. Rates of elimination and volumes of distribution were found to be significantly increased in the patients (0.0797 + 0.0143 h-' and 0.175 0.025 1/kg respectively) as compared to normal subjects. Results of this study will be reported in detail in a separate article (Perucca, Gatti, Frigo, Crema, Calzetti & Visintini, 1978).

PERUCCA, E., GATTI, G., FRIGO, G.M., CREMA, A.,

CALZETTI, S. & VISINTINI, D. (1978). Disposition of valproic acid in epileptic patients. Br. J. clin. Pharnnac. (in press).