British Journal of Obstetrics and Gytiaecology February 1979. Vol86. pp 125-1 32
METABOLISM OF DIPHENYLHYDANTOIN (PHENYTOIN) DURING PREGNANCY BY
M. J. LANDON* AND
MAUREEN KIRKLEY M . R . C . Reproduction and Growth Research Unit, Princess Mary Maternity Hospital Great North Road, Newcastle-upon-Tyne, NE2 3BD
Summary Plasma levels of diphenylhydantoin (DPH) and the 24 hour urinary excretion of both DPH and its major metabolite 5-(p-hydroxyphenyl)-phenylhydantoin (HPPH) were measured serially during pregnancy in a group of five unselected epileptic patients. Plasma DPH levels fell and on average were some 40 per cent lower at term than they had been in early pregnancy. With one exception, the patients were well controlled during pregnancy but two patients who regularly had plasma DPH levels below 10 pg/ml both suffered seizures in the puerperium. There was no convincing change in the excretion of either DPH or HPPH which together accounted for less than half the administered dose. Gestational length exceeded 41 weeks in 4 of the 5 patients studied but a11 were delivered of normal healthy infants, of average birthweight, with no congenital defects or clotting disorders. A RECENT survey of epileptic patients suggested that half of them may experience more fits during pregnancy (Knight and Rhind, 1975). A variety of reasons have been put forward to explain this tendency and recent reports suggest that plasma levels of anticonvulsants may be lower during pregnancy (Mygind et al, 1976; Lander et al, 1977) but surprisingly there are no published data on the metabolism of anticonvulsants. Pregnancy is characterized by general changes in absorption, excretion and metabolism and it would be surprising if drugs such as anticonvulsants were not themselves affected in consequence. We report here a study of one
major anticonvulsant, diphenylhydantoin (DPH) (Phenytoin sodium, Epanutin, Dilantin), during pregnancy.
METHODS Five epileptic patients, all on long term DPH therapy, were studied serially during pregnancy and the puerperium. They were seen regularly throughout pregnancy at a routine antenatal clinic but any questions relating to the management of their epilepsy were referred to a neurologist independent of the study. Brief details of the patients involved are given in Table I. With one exception (Patient 5 ) all remained well controlled throughout pregnancy and consequently their treatment remained unaltered. Each patient collected all urine passed during the 24 hours preceding her routine antenatal
* Present
address: Division of Perinatal Medicine, Clinical Research Centre, Watford Road, Harrow, HA1 3UJ, Middlesex. 125
126
LANDON AND KIRKLEY
TABLE I Patients taking diphenylhydantoin ( D P H ) during pregnatrcj~ Daily dose of DPH (mg)
Weight
Other drugs
Patient
Age (years)
1
23
0
+0
300
49.6
Phenobarbitone
2
27
0 + 2
300
56.3
Mysoline
3
17
0
+
0
200
74.9
Phenobarbitone
30 rng thrice daily
Iron and folic acid
4
22
1 1 0
100
51.9
Phenobarbitone
60 mg at night
Iron and folic acid
5
23
O i l
300
49.6
Phenobarbitone
30 mg thrice daily
None
Carbamazepine
50 rng thrice daily
None
Parity
5 (from 32 weeks gestation)
0%)
400
clinic visit into a polythene bottle containing a few drops of five per cent aqueous hibitane as preservative. The volume was subsequently measured and an aliquot stored frozen for later analysis. At the clinic, 10 ml of venous blood were collected into a heparinized tube at approximately the same time each visit, plasma was prepared as soon as possible by centrifugation and stored frozen. Similar samples of both maternal and cord blood were collected at delivery together with an aliquot of amniotic fluid and the placenta if available. DPH was measured by the method of Barrett (1971) and its major metabolite, 5-(p-hydroxypheny1)-phenylhydantoin (HPPH) by the method of Chang and Glazko (1970). Derivatives of both were formed by on-column methylation using tri-methylanilinium hydroxide. A Pye Unicam 106 gas chromatograph with flame ionisation detectors was used throughout. Glass columns, six feet by 0-25 inches were packed with 3 per cent OV 17 on Gas Chrom Q 80-100 mesh and operated at 225°C for DPH and 250°C for HPPH. Injection and detector temperatures were set at 300°C for both compounds and the carrier gas was oxygen free nitrogen flowing at 40 ml/minute. Using this system the coefficient of variation between assays was 6.5 per cent for DPH and 14 per cent for HPPH. RESULTS In the four patients whose treatment remained unchanged, plasma DPH levels fell during
Anticonvulsants 30 mg thrice daily 250 mg thrice daily
Haematinics None
Iron only
-
pregnancy. One week after delivery, plasma levels were still low and although eight weeks later they had risen they were, with one exception, still below the levels found in early pregnancy. There was considerable individual variation but in general each patient followed the trend suggested by the mean (Fig. 1). Excretion of DPH in a 24-hour urine collection was small and on average less than one per cent of the daily administered dose was recovered. Again there was considerable individual variation and in two patients (No. 3 and 4) there were occasions when a 24-hour collection contained no detectable DPH (Fig. 2). There was no relation between urine DPH levels and either urine volume or glomerular filtration rate as measured by 24-hour creatinine clearance (Table 11). In general plasma and urine levels of DPH reflected the dose of the drug prescribed. On average, 38 per cent of the prescribed dose was recovered as the metabolite HPPH ; the higher the dose of DPH the greater the amount of HPPH excreted per 24 hours but the percentage recovered decreased with increasing dose (Fig. 3). There was no convincing change in HPPH excretion during pregnancy and the renal losses were unrelated to either urine volume or glomerular filtration rate (Table 11). Patient No. 5 complained of ‘funny turns’ and ‘dizzy spells’ from about 24 weeks gestation although no classical epileptiform attacks were ever witnessed by the medical staff. Her daily phenytoin intake was increased empirically by 100 mg without noticeable effect on either the
PHENYTOIN METABOLISM
-4
*Ol
delivery
antenatal
I
I
I
24
I
1
......... postnatal
I
1
I
8 wks P.P.
40
32 weeks gestation FIG.1
Plasma levels of diphenylhydantoin during pregnancy and the puerperium.
delivery
-4 ........... antenatal
postnotal
X-none detected .
_ _ - - -... v
.-.-.:I _____---a __ ____. --.---
........
I
24
I
1
I
32
1
40
-r
a wks FP.
weeks gestation FIG.
2
Excretion of diphenylhydantoin during pregnancy and 8 weeks post partum.
127
128
LANDON AND KIRKLEY
TABLE II Excretion of DPH during and after pregnarrcy by four parients whose treatment remained unchanged during and after pregnancy 24-hour urine volume (ml)
HPPH total (mg)
Creatinine clearance (rnl/minute)
54 78 60 72 48
1650 1900 1300 1575 1650 1100 1075 1400 1550
56 106 75 69 89 86 64 101 74
151 102 89 57 120 56 82 94 92
73 81 54 54 75 59 51 67 58 86
1340 1375 2054 2050 2255 1860 1900 1650 1800 1950
98 111 111 111 I 69 110 97 110 104 168
103 148 184 162 158 159 204 179 118 125
64 195 64 62 122 56 62 54 88
950 500 1250 1375 660 1275 1300 1450 2100
61 98 80 85 80 71 80 78 185
122 134 97 96 122 87 100 117 159
750 1350 1130 1690 1540 1350 1325 1440 1500 1350
45 50 45 27 55 42 37 63 60 35
52 85 87 86 93 141 162 141 112 62
DPH ( d m l ) HPPH
Patient No. 1
Patient No. 2
Patient No. 3
Gestation (weeks)
Plasma
Urine
(rns/l)
28 30 32 34 36 38 41 42 8 weeks post partuni
18.0 15.5 16.5 14.5 12.0 14.5 15.5 14.5
2.0 3.5 3.0 0.5 2-5 2.5 3.0 3.5 2.0
34 56 58
23 31 33 35 36 31 38 39 40 8 weeks post partum
12.0 9.5
8.5 7.1 7.5 9.0
4.0 1.5 2.5 3.5 5.0 4.0 4.5 4.0 1.0 2.0
33 35 36 37 38 39 40 41 8 weeks post parturn
3.0 4.5 3.5 4.5 2.0 1.5 2.0 3.0 4.5
0.5 1.0 1.0 nd 0.5 nd nd nd 2.0
26 28 31 34 36 38 39 40
5.0 6.0 2.0 2.0 3.0 2.0 1.0 3.0 3.0 5.0
0.5 0.5 nd 1.0 nd 0.5 0.5 nd
Patient No. 4
41
8 weeks post partum nd
=
8.0
8.0
8.5 8.0 8.0
60 37 40 16 36 31 28
44
1-0 1.5
44
40 26
none detected
plasma level of DPH or her symptomatology and a fortnight later carbamazepine was substituted for phenobarbitone (Fig. 4). Because of her history of poor control of epilepsy, this patient was induced at 38 weeks gestation by amniotomy and oxytocin.
The remaining patients in the group were allowed to go to term and all were delivered of normal healthy infants with neither congenital abnormalities nor bleeding disorders (Table 111). Details of DPH levels at delivery are given in Table IV.
PHENYTOIN METABOLISM
200-
.-L 1503
i
c
U \
1OQ
F I:
2
-J:--
5a.
I'
0
0
NO. 4
0-
Excretion of 5-(p-hydroxyphenyl)-phenylhydantoin (HPPH) during pregnancy (solid circles) and 8 weeks post partum (open circles). Horizontal pecked line represents mean excretion during pregnancy. Postpartum value for Patient No. 3 has been omitted because additional phenytoin was prescribed after delivery.
-
20-
plasma DPH ug/rnl
-
15-
urine DPH mg/ ZLhrs
10x-x urine HPPH rng/2Lhrsx10-'
5-
to o :o o o o :o
I
000000000000 0000 00000000
I
24
I
+ + + +
+ + +
+ + + + + + +
00
+ + + +
I
+ +
I
32 weeks gestation FIG.4
+ + + * + + + + 1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
I
40
7
8 wks P.P.
Plasma levels of DPH and excretion of DPH and HPPH in Patient No. 5. 6
129
130
LANDON AND KIRKLEY
TABLE I11 Details of delivery
Patient No.
Gestation (weeks)
Induction to delivery interval (hours)
Induction
Birth weight (kg)
Method of delivery
~
Sex
~
1
43
Yes
82
Spontaneousvertex
3.43
Male
2
41
No
(322)
Spontaneousvertex
3.20
Female
3
42
No
(1724
Keillands forceps
3.42
Female
4
41
Yes
8t
Spontaneousvertex
3.02
Female
5
38
YeS
4%
Barnes forceps
3.48
Male
TABLE IV Diphenylhydantoin levels at delivery Patient No.
Maternal plasma (i*g/ml)
Cord plasma (Pg/ml)
Amniotic fluid (Pg/ml>
Placenta (Pg/g)
Placenta total (mg)
1
13.5
13.5
4.5
8.0
5.3
2
7.0
7.5
4.5
5.5
3.4
3
0-5
0.5
nd
6.5
4.4
4
3.0
2.0
3.5
10.0
5.6
5
11.5
7.5
1.5
17.5
14.3
~~
~
nd = none detected
DISCUSSION In every patient plasma levels of DPH fell below the commonly accepted therapeutic minimum of 10 pg/ml (Buchthal et al, 1960; Lund, 1974) at some point in this study. Although the advent of routine anticonvulsant assays has shown that in many patients effective control can be maintained with drug levels of less than 10 pg/ml (Reynolds et al, 1976) yet a drop in plasma concentration of some 40 per cent must compromise control in some patients. In fact, two patients in the present series (No. 3 and 4) suffered grand ma1 seizures in the immediate postnatal period, and in Patient No. 3 the daily intake of DPH was increased by 100 mg as a result. Small differences in sampling time and time of medication may account for some of the individual variations in plasma DPH levels but we do not think that the falling plasma
levels resulted from failure of the patients to take their prescribed medication. No patient defaulted, all were very co-operative and all were acutely aware of the danger to the fetus of a grand ma1 attack. Furthermore, there was no significant change in the excretion of HPPH over the period studied. The normal physiological increase in blood volume during pregnancy may in part be responsible for the reduced concentrations of DPH. However, assuming an average increase in plasma volume of 750 ml over the period studied, calculation of the total circulating mass of DPH still gives lower results as pregnancy progresses. An increase in the distribution space of some 6 1 would be needed to entirely account for the fall in plasma concentration. The increase in the interstitial fluid volume during pregnancy may be of this order. It seems unlikely that the renal losses of DPH
PHENYTOIN METABOLISM
made a significant contribution to the falling plasma levels in the present series. There was no convincing change in DPH excretion during or after pregnancy and in general the greater the dose of DPH prescribed the more DPH was excreted. It is difficult to draw conclusions from such a small series-only two patients (No. 1 and 2) were taking the same dose of Epanutin (300 mg per day). These two patients had significantly different mean plasma DPH levels but there was no significant difference in 24-hour DPH excretion, urine volume or glomerular filtration rate. There was, however, a significant difference in their excretion of HPPH which presumably reflected different rates of metabolism. Presumably only ‘free’ DPH is filtered through the glomerulus and in non-pregnant subjects this may be only 10 per cent of the total in plasma. In vitro studies suggest that there is no significant change in the capacity of plasma proteins to bind DPH during pregnancy but if albumin is the major carrier protein then the falling plasma albumin concentration could increase the proportion of ‘free’ DPH (Hooper et al, 1974). If the ‘free’ DPH is the therapeutically effective fraction, then it may be significant that the two patients who suffered epileptic attacks in the puerperium excreted no DPH during a 24-hour urine collection on one or more occasions in the previous month. It seems reasonable to assume from this that there was little or no free DPH available for filtration at the glomerulus, that tissue levels had gradually become depleted and seizure control was eventually compromised. Excretion of DPH in 24-hour urine collections may therefore be a measure of the plasma levels of free DPH and as such serve as a useful clinical index of effective therapy. Indeed, examination of the data provided by Bochner et a1 (1973) supports this thesis: in their series of 16 patients there was a highly significant correlation between plasma free DPH and DPH excreted in a timed urine collection. The concentration of DPH in a saliva sample has also been used as a measure of ‘free’ plasma DPH levels but a urine collection has the advantage that it can effectively ‘average’ the free plasma DPH level over a 24-hour period. It was anticipated that changes in metabolism would amost certainly contribute to the altered
131
picture of DPH levels during pregnancy. A number of studies have demonstrated similarities between enzyme systems which hydroxylate steroids and those which oxidise drugs: steroid hormones may well be the natural substrate for drug metabolizing enzymes of the hepatic microsomes (Kuntzman, 1969). Direct evidence in the case of DPH is scanty. In general, epileptic women appear to need higher doses of anticonvulsants than men to achieve effective control (Travers et al, 1972) and there are isolated reports of the failure of oral contraception amongst these patients. The administration of oestrogens to healthy male volunteers can reduce the half-life of acutely administered DPH (Fernandez-Pol and Zaninovich, 1975). Metabolism of DPH during pregnancy may be considerably influenced by the high levels of endogenous steroids at this time. It was noticeable that in the group studied, plasma levels of DPH eight weeks after delivery were still lower than they had been in early pregnancy. The possibility exists that in some individuals early pregnancy is associated with a rise in plasma DPH levels because of competition from endogenous steroids for the main metabolic pathways. This may be particularly relevant to the incidence of congenital abnormalities where high levels of DPH have been implicated (Richens and Houghton, 1973; Loughnan et al, 1973). A high capacity to handle steroids which persists in the early puerperium may explain the low plasma levels of DPH found in some patients at this time, for example plasma levels in Patient No. 5 fell by over 50 per cent within 24 hours of delivery. If the excretion of HPPH is a realistic index of DPH metabolism during pregnancy, then there does not appear to have been any significant change throughout the period studied. HPPH is excreted via the kidney and the enhanced renal function characteristic of pregnancy would be more than adequate to handle any increase in HPPH production. Admittedly the percentage of the administered dose recovered as HPPH is rather lower in this series than has been reported in the literature for non-pregnant subjects (Glazko et al, 1969). Traditionally, low HPPH excretion and falling plasma DPH levels would suggest poor patient compliance but it may be that either malabsorption of this drug in
132
LANDON AND KIRKLEY
pregnancy is rather more widespread than the one case reported by Ramsay et aZ(1978) would indicate or that the metabolism and disposition of this drug is not as straightforward as generally assumed. Unfortunately no data are available on the excretion of HPPH either during the puerperium or in very early pregnancy so the possibility of abrupt changes in metabolism at these times remains conjectural. Whatever the explanation, data from the present study suggest that plasma DPH levels may fall by some 40 per cent during pregnancy and that patients may be particularly at risk during the immediate post-delivery period. Because of wide individual variations in DPH metabolism it is difficult to draw general conclusions about the management of epileptics during pregnancy. If it is realistic to apply the nomogram of Richens and Dunlop (1975) to this situation then an additional 50 to 100 mg DPH per day may be sufficient to compensate for the changes observed in pregnancy. Such additional medication may, however, produce toxic levels in the puerperium. Careful supervision of the patient and regular monitoring of plasma drug levels are obviously indicated. REFERENCES Barrett, J. M. (1971): Clinical Chemistry Newsletter, 3,16. Bochner, F., Hooper, W. D., Sutherland, J. M., Eadie, M. J., and Tyrer, J. H. (1973): ClinicalPharmacology and Therapeutics, 15,276.
Buchthal, F., Svensmark, D., and Schiller, P. J. (1960): Archives of Neurology, 2,624. Chang, T., and Glazko, A. J. (1970): Journal of Laboratory and Clinical Medicine, 75,145. Fernandez-Pol, J. A,, and Zaninovich, A. A. (1975): JournalofNuclear Medicine, 16,305. Glazko, A. J., Chang, T., Baukema, J., Dill, W. A., Goulet, J. R. and Buchanan, R. A. (1969): Clinical Pharmacology and Therapeutics, 10,498.
Hooper, W. D., Bochner, F., Eadie, M. J., and Tyrer, J. H. (1 974) : Clinical Pharmacology and Therapeutics, 15,276. Knight, A. H., and Rhind, E. G. (1975): Epilepsia, 16, 99. Kuntzman,J. (1969): Pharmacological Reviews, 9,21. Lander, C. M., Edwards, V. E., Eadie, M. J., and Tyrer, J. H. (1977): Neurology, 27,128. Loughnan, P. M., Gold, H. M., and Vance, J. C. (1973): Lancet, 1,70. Lund, L. (1974): Archives of Neurology, 31,289. Mygind, K. I., Dam, M., and Christiansen, J. (1976): Acta neurologica Scandinavica, 54,160. Ramsay, R. E., Strauss, R. G., Wilder, B. J., and Willmore, L. J. (1978): Neurology, 28,85. Reynolds, E. H., Chadwick, D., and Galbraith, A. W. (1976): Lancet, 1,923. Richens, A., and Dunlop, A. (1975): Lancet, 2,247. Richens, A., and Houghton, G. W. (1973): British Medical Journal, 1,544. Travers, R. D., Reynolds, E. H., and Gallagher, B. B. (1972): Archives of Neurology, 27,29.
METABOLISM OF DIPHENYLHYDANTOIN (PHENYTOIN) DURING PREGNANCY BY
M. J. LANDON* AND
MAUREEN KIRKLEY M . R . C . Reproduction and Growth Research Unit, Princess Mary Maternity Hospital Great North Road, Newcastle-upon-Tyne, NE2 3BD
Summary Plasma levels of diphenylhydantoin (DPH) and the 24 hour urinary excretion of both DPH and its major metabolite 5-(p-hydroxyphenyl)-phenylhydantoin (HPPH) were measured serially during pregnancy in a group of five unselected epileptic patients. Plasma DPH levels fell and on average were some 40 per cent lower at term than they had been in early pregnancy. With one exception, the patients were well controlled during pregnancy but two patients who regularly had plasma DPH levels below 10 pg/ml both suffered seizures in the puerperium. There was no convincing change in the excretion of either DPH or HPPH which together accounted for less than half the administered dose. Gestational length exceeded 41 weeks in 4 of the 5 patients studied but a11 were delivered of normal healthy infants, of average birthweight, with no congenital defects or clotting disorders. A RECENT survey of epileptic patients suggested that half of them may experience more fits during pregnancy (Knight and Rhind, 1975). A variety of reasons have been put forward to explain this tendency and recent reports suggest that plasma levels of anticonvulsants may be lower during pregnancy (Mygind et al, 1976; Lander et al, 1977) but surprisingly there are no published data on the metabolism of anticonvulsants. Pregnancy is characterized by general changes in absorption, excretion and metabolism and it would be surprising if drugs such as anticonvulsants were not themselves affected in consequence. We report here a study of one
major anticonvulsant, diphenylhydantoin (DPH) (Phenytoin sodium, Epanutin, Dilantin), during pregnancy.
METHODS Five epileptic patients, all on long term DPH therapy, were studied serially during pregnancy and the puerperium. They were seen regularly throughout pregnancy at a routine antenatal clinic but any questions relating to the management of their epilepsy were referred to a neurologist independent of the study. Brief details of the patients involved are given in Table I. With one exception (Patient 5 ) all remained well controlled throughout pregnancy and consequently their treatment remained unaltered. Each patient collected all urine passed during the 24 hours preceding her routine antenatal
* Present
address: Division of Perinatal Medicine, Clinical Research Centre, Watford Road, Harrow, HA1 3UJ, Middlesex. 125
126
LANDON AND KIRKLEY
TABLE I Patients taking diphenylhydantoin ( D P H ) during pregnatrcj~ Daily dose of DPH (mg)
Weight
Other drugs
Patient
Age (years)
1
23
0
+0
300
49.6
Phenobarbitone
2
27
0 + 2
300
56.3
Mysoline
3
17
0
+
0
200
74.9
Phenobarbitone
30 rng thrice daily
Iron and folic acid
4
22
1 1 0
100
51.9
Phenobarbitone
60 mg at night
Iron and folic acid
5
23
O i l
300
49.6
Phenobarbitone
30 mg thrice daily
None
Carbamazepine
50 rng thrice daily
None
Parity
5 (from 32 weeks gestation)
0%)
400
clinic visit into a polythene bottle containing a few drops of five per cent aqueous hibitane as preservative. The volume was subsequently measured and an aliquot stored frozen for later analysis. At the clinic, 10 ml of venous blood were collected into a heparinized tube at approximately the same time each visit, plasma was prepared as soon as possible by centrifugation and stored frozen. Similar samples of both maternal and cord blood were collected at delivery together with an aliquot of amniotic fluid and the placenta if available. DPH was measured by the method of Barrett (1971) and its major metabolite, 5-(p-hydroxypheny1)-phenylhydantoin (HPPH) by the method of Chang and Glazko (1970). Derivatives of both were formed by on-column methylation using tri-methylanilinium hydroxide. A Pye Unicam 106 gas chromatograph with flame ionisation detectors was used throughout. Glass columns, six feet by 0-25 inches were packed with 3 per cent OV 17 on Gas Chrom Q 80-100 mesh and operated at 225°C for DPH and 250°C for HPPH. Injection and detector temperatures were set at 300°C for both compounds and the carrier gas was oxygen free nitrogen flowing at 40 ml/minute. Using this system the coefficient of variation between assays was 6.5 per cent for DPH and 14 per cent for HPPH. RESULTS In the four patients whose treatment remained unchanged, plasma DPH levels fell during
Anticonvulsants 30 mg thrice daily 250 mg thrice daily
Haematinics None
Iron only
-
pregnancy. One week after delivery, plasma levels were still low and although eight weeks later they had risen they were, with one exception, still below the levels found in early pregnancy. There was considerable individual variation but in general each patient followed the trend suggested by the mean (Fig. 1). Excretion of DPH in a 24-hour urine collection was small and on average less than one per cent of the daily administered dose was recovered. Again there was considerable individual variation and in two patients (No. 3 and 4) there were occasions when a 24-hour collection contained no detectable DPH (Fig. 2). There was no relation between urine DPH levels and either urine volume or glomerular filtration rate as measured by 24-hour creatinine clearance (Table 11). In general plasma and urine levels of DPH reflected the dose of the drug prescribed. On average, 38 per cent of the prescribed dose was recovered as the metabolite HPPH ; the higher the dose of DPH the greater the amount of HPPH excreted per 24 hours but the percentage recovered decreased with increasing dose (Fig. 3). There was no convincing change in HPPH excretion during pregnancy and the renal losses were unrelated to either urine volume or glomerular filtration rate (Table 11). Patient No. 5 complained of ‘funny turns’ and ‘dizzy spells’ from about 24 weeks gestation although no classical epileptiform attacks were ever witnessed by the medical staff. Her daily phenytoin intake was increased empirically by 100 mg without noticeable effect on either the
PHENYTOIN METABOLISM
-4
*Ol
delivery
antenatal
I
I
I
24
I
1
......... postnatal
I
1
I
8 wks P.P.
40
32 weeks gestation FIG.1
Plasma levels of diphenylhydantoin during pregnancy and the puerperium.
delivery
-4 ........... antenatal
postnotal
X-none detected .
_ _ - - -... v
.-.-.:I _____---a __ ____. --.---
........
I
24
I
1
I
32
1
40
-r
a wks FP.
weeks gestation FIG.
2
Excretion of diphenylhydantoin during pregnancy and 8 weeks post partum.
127
128
LANDON AND KIRKLEY
TABLE II Excretion of DPH during and after pregnarrcy by four parients whose treatment remained unchanged during and after pregnancy 24-hour urine volume (ml)
HPPH total (mg)
Creatinine clearance (rnl/minute)
54 78 60 72 48
1650 1900 1300 1575 1650 1100 1075 1400 1550
56 106 75 69 89 86 64 101 74
151 102 89 57 120 56 82 94 92
73 81 54 54 75 59 51 67 58 86
1340 1375 2054 2050 2255 1860 1900 1650 1800 1950
98 111 111 111 I 69 110 97 110 104 168
103 148 184 162 158 159 204 179 118 125
64 195 64 62 122 56 62 54 88
950 500 1250 1375 660 1275 1300 1450 2100
61 98 80 85 80 71 80 78 185
122 134 97 96 122 87 100 117 159
750 1350 1130 1690 1540 1350 1325 1440 1500 1350
45 50 45 27 55 42 37 63 60 35
52 85 87 86 93 141 162 141 112 62
DPH ( d m l ) HPPH
Patient No. 1
Patient No. 2
Patient No. 3
Gestation (weeks)
Plasma
Urine
(rns/l)
28 30 32 34 36 38 41 42 8 weeks post partuni
18.0 15.5 16.5 14.5 12.0 14.5 15.5 14.5
2.0 3.5 3.0 0.5 2-5 2.5 3.0 3.5 2.0
34 56 58
23 31 33 35 36 31 38 39 40 8 weeks post partum
12.0 9.5
8.5 7.1 7.5 9.0
4.0 1.5 2.5 3.5 5.0 4.0 4.5 4.0 1.0 2.0
33 35 36 37 38 39 40 41 8 weeks post parturn
3.0 4.5 3.5 4.5 2.0 1.5 2.0 3.0 4.5
0.5 1.0 1.0 nd 0.5 nd nd nd 2.0
26 28 31 34 36 38 39 40
5.0 6.0 2.0 2.0 3.0 2.0 1.0 3.0 3.0 5.0
0.5 0.5 nd 1.0 nd 0.5 0.5 nd
Patient No. 4
41
8 weeks post partum nd
=
8.0
8.0
8.5 8.0 8.0
60 37 40 16 36 31 28
44
1-0 1.5
44
40 26
none detected
plasma level of DPH or her symptomatology and a fortnight later carbamazepine was substituted for phenobarbitone (Fig. 4). Because of her history of poor control of epilepsy, this patient was induced at 38 weeks gestation by amniotomy and oxytocin.
The remaining patients in the group were allowed to go to term and all were delivered of normal healthy infants with neither congenital abnormalities nor bleeding disorders (Table 111). Details of DPH levels at delivery are given in Table IV.
PHENYTOIN METABOLISM
200-
.-L 1503
i
c
U \
1OQ
F I:
2
-J:--
5a.
I'
0
0
NO. 4
0-
Excretion of 5-(p-hydroxyphenyl)-phenylhydantoin (HPPH) during pregnancy (solid circles) and 8 weeks post partum (open circles). Horizontal pecked line represents mean excretion during pregnancy. Postpartum value for Patient No. 3 has been omitted because additional phenytoin was prescribed after delivery.
-
20-
plasma DPH ug/rnl
-
15-
urine DPH mg/ ZLhrs
10x-x urine HPPH rng/2Lhrsx10-'
5-
to o :o o o o :o
I
000000000000 0000 00000000
I
24
I
+ + + +
+ + +
+ + + + + + +
00
+ + + +
I
+ +
I
32 weeks gestation FIG.4
+ + + * + + + + 1 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
I
40
7
8 wks P.P.
Plasma levels of DPH and excretion of DPH and HPPH in Patient No. 5. 6
129
130
LANDON AND KIRKLEY
TABLE I11 Details of delivery
Patient No.
Gestation (weeks)
Induction to delivery interval (hours)
Induction
Birth weight (kg)
Method of delivery
~
Sex
~
1
43
Yes
82
Spontaneousvertex
3.43
Male
2
41
No
(322)
Spontaneousvertex
3.20
Female
3
42
No
(1724
Keillands forceps
3.42
Female
4
41
Yes
8t
Spontaneousvertex
3.02
Female
5
38
YeS
4%
Barnes forceps
3.48
Male
TABLE IV Diphenylhydantoin levels at delivery Patient No.
Maternal plasma (i*g/ml)
Cord plasma (Pg/ml)
Amniotic fluid (Pg/ml>
Placenta (Pg/g)
Placenta total (mg)
1
13.5
13.5
4.5
8.0
5.3
2
7.0
7.5
4.5
5.5
3.4
3
0-5
0.5
nd
6.5
4.4
4
3.0
2.0
3.5
10.0
5.6
5
11.5
7.5
1.5
17.5
14.3
~~
~
nd = none detected
DISCUSSION In every patient plasma levels of DPH fell below the commonly accepted therapeutic minimum of 10 pg/ml (Buchthal et al, 1960; Lund, 1974) at some point in this study. Although the advent of routine anticonvulsant assays has shown that in many patients effective control can be maintained with drug levels of less than 10 pg/ml (Reynolds et al, 1976) yet a drop in plasma concentration of some 40 per cent must compromise control in some patients. In fact, two patients in the present series (No. 3 and 4) suffered grand ma1 seizures in the immediate postnatal period, and in Patient No. 3 the daily intake of DPH was increased by 100 mg as a result. Small differences in sampling time and time of medication may account for some of the individual variations in plasma DPH levels but we do not think that the falling plasma
levels resulted from failure of the patients to take their prescribed medication. No patient defaulted, all were very co-operative and all were acutely aware of the danger to the fetus of a grand ma1 attack. Furthermore, there was no significant change in the excretion of HPPH over the period studied. The normal physiological increase in blood volume during pregnancy may in part be responsible for the reduced concentrations of DPH. However, assuming an average increase in plasma volume of 750 ml over the period studied, calculation of the total circulating mass of DPH still gives lower results as pregnancy progresses. An increase in the distribution space of some 6 1 would be needed to entirely account for the fall in plasma concentration. The increase in the interstitial fluid volume during pregnancy may be of this order. It seems unlikely that the renal losses of DPH
PHENYTOIN METABOLISM
made a significant contribution to the falling plasma levels in the present series. There was no convincing change in DPH excretion during or after pregnancy and in general the greater the dose of DPH prescribed the more DPH was excreted. It is difficult to draw conclusions from such a small series-only two patients (No. 1 and 2) were taking the same dose of Epanutin (300 mg per day). These two patients had significantly different mean plasma DPH levels but there was no significant difference in 24-hour DPH excretion, urine volume or glomerular filtration rate. There was, however, a significant difference in their excretion of HPPH which presumably reflected different rates of metabolism. Presumably only ‘free’ DPH is filtered through the glomerulus and in non-pregnant subjects this may be only 10 per cent of the total in plasma. In vitro studies suggest that there is no significant change in the capacity of plasma proteins to bind DPH during pregnancy but if albumin is the major carrier protein then the falling plasma albumin concentration could increase the proportion of ‘free’ DPH (Hooper et al, 1974). If the ‘free’ DPH is the therapeutically effective fraction, then it may be significant that the two patients who suffered epileptic attacks in the puerperium excreted no DPH during a 24-hour urine collection on one or more occasions in the previous month. It seems reasonable to assume from this that there was little or no free DPH available for filtration at the glomerulus, that tissue levels had gradually become depleted and seizure control was eventually compromised. Excretion of DPH in 24-hour urine collections may therefore be a measure of the plasma levels of free DPH and as such serve as a useful clinical index of effective therapy. Indeed, examination of the data provided by Bochner et a1 (1973) supports this thesis: in their series of 16 patients there was a highly significant correlation between plasma free DPH and DPH excreted in a timed urine collection. The concentration of DPH in a saliva sample has also been used as a measure of ‘free’ plasma DPH levels but a urine collection has the advantage that it can effectively ‘average’ the free plasma DPH level over a 24-hour period. It was anticipated that changes in metabolism would amost certainly contribute to the altered
131
picture of DPH levels during pregnancy. A number of studies have demonstrated similarities between enzyme systems which hydroxylate steroids and those which oxidise drugs: steroid hormones may well be the natural substrate for drug metabolizing enzymes of the hepatic microsomes (Kuntzman, 1969). Direct evidence in the case of DPH is scanty. In general, epileptic women appear to need higher doses of anticonvulsants than men to achieve effective control (Travers et al, 1972) and there are isolated reports of the failure of oral contraception amongst these patients. The administration of oestrogens to healthy male volunteers can reduce the half-life of acutely administered DPH (Fernandez-Pol and Zaninovich, 1975). Metabolism of DPH during pregnancy may be considerably influenced by the high levels of endogenous steroids at this time. It was noticeable that in the group studied, plasma levels of DPH eight weeks after delivery were still lower than they had been in early pregnancy. The possibility exists that in some individuals early pregnancy is associated with a rise in plasma DPH levels because of competition from endogenous steroids for the main metabolic pathways. This may be particularly relevant to the incidence of congenital abnormalities where high levels of DPH have been implicated (Richens and Houghton, 1973; Loughnan et al, 1973). A high capacity to handle steroids which persists in the early puerperium may explain the low plasma levels of DPH found in some patients at this time, for example plasma levels in Patient No. 5 fell by over 50 per cent within 24 hours of delivery. If the excretion of HPPH is a realistic index of DPH metabolism during pregnancy, then there does not appear to have been any significant change throughout the period studied. HPPH is excreted via the kidney and the enhanced renal function characteristic of pregnancy would be more than adequate to handle any increase in HPPH production. Admittedly the percentage of the administered dose recovered as HPPH is rather lower in this series than has been reported in the literature for non-pregnant subjects (Glazko et al, 1969). Traditionally, low HPPH excretion and falling plasma DPH levels would suggest poor patient compliance but it may be that either malabsorption of this drug in
132
LANDON AND KIRKLEY
pregnancy is rather more widespread than the one case reported by Ramsay et aZ(1978) would indicate or that the metabolism and disposition of this drug is not as straightforward as generally assumed. Unfortunately no data are available on the excretion of HPPH either during the puerperium or in very early pregnancy so the possibility of abrupt changes in metabolism at these times remains conjectural. Whatever the explanation, data from the present study suggest that plasma DPH levels may fall by some 40 per cent during pregnancy and that patients may be particularly at risk during the immediate post-delivery period. Because of wide individual variations in DPH metabolism it is difficult to draw general conclusions about the management of epileptics during pregnancy. If it is realistic to apply the nomogram of Richens and Dunlop (1975) to this situation then an additional 50 to 100 mg DPH per day may be sufficient to compensate for the changes observed in pregnancy. Such additional medication may, however, produce toxic levels in the puerperium. Careful supervision of the patient and regular monitoring of plasma drug levels are obviously indicated. REFERENCES Barrett, J. M. (1971): Clinical Chemistry Newsletter, 3,16. Bochner, F., Hooper, W. D., Sutherland, J. M., Eadie, M. J., and Tyrer, J. H. (1973): ClinicalPharmacology and Therapeutics, 15,276.
Buchthal, F., Svensmark, D., and Schiller, P. J. (1960): Archives of Neurology, 2,624. Chang, T., and Glazko, A. J. (1970): Journal of Laboratory and Clinical Medicine, 75,145. Fernandez-Pol, J. A,, and Zaninovich, A. A. (1975): JournalofNuclear Medicine, 16,305. Glazko, A. J., Chang, T., Baukema, J., Dill, W. A., Goulet, J. R. and Buchanan, R. A. (1969): Clinical Pharmacology and Therapeutics, 10,498.
Hooper, W. D., Bochner, F., Eadie, M. J., and Tyrer, J. H. (1 974) : Clinical Pharmacology and Therapeutics, 15,276. Knight, A. H., and Rhind, E. G. (1975): Epilepsia, 16, 99. Kuntzman,J. (1969): Pharmacological Reviews, 9,21. Lander, C. M., Edwards, V. E., Eadie, M. J., and Tyrer, J. H. (1977): Neurology, 27,128. Loughnan, P. M., Gold, H. M., and Vance, J. C. (1973): Lancet, 1,70. Lund, L. (1974): Archives of Neurology, 31,289. Mygind, K. I., Dam, M., and Christiansen, J. (1976): Acta neurologica Scandinavica, 54,160. Ramsay, R. E., Strauss, R. G., Wilder, B. J., and Willmore, L. J. (1978): Neurology, 28,85. Reynolds, E. H., Chadwick, D., and Galbraith, A. W. (1976): Lancet, 1,923. Richens, A., and Dunlop, A. (1975): Lancet, 2,247. Richens, A., and Houghton, G. W. (1973): British Medical Journal, 1,544. Travers, R. D., Reynolds, E. H., and Gallagher, B. B. (1972): Archives of Neurology, 27,29.
