0/O
Barbiturates. Structural Comparisons. Amobarbital, JIethplamobarbital, and Bute
amohdrbitdl i11 0
methylamobarbital (11)
NOTES
March 1969
331
I
I
2 0
I-
280
240
-5
-
-
5
200-
w
5
-
ff
f
160-
w
oi
a
-
1
w
I20
-
80
-
40-
A M B Na
CHz.AMB
Figure Z.-Effect of B-diethylaminoethyl iiphenylpropylacetate (SKF-525A) and iproniazide on the duration of action of equimolar doses (0.28 mmole/kg ip) of amobarbital (AMB.Na) (70 mg/kg) and methylamobarbital (CHSAMB) (67.5 mg/kg) in male mice. @-Diethylaminoethyl diphenylpropylacetate (10 mg/kg ip) ( m ) was given 60 min prior to and iproniazide phosphate (100 mg/kg ip) (GI) 30 min prior to the administration of barbiturates. Control animals received saline ( 5 ml/kg ip) (0).Each group consisted of ten animals.
Figure 3.-Efect of p-diethylaminoethyl diphenylpropylacetate and iproniazide on the duration of action of equimolar doses (0.28 mmole/kg ip) of amobarbital (AMB.Na) (70 mg/kg) and methylamobarbital (CHsAMB) (67.5 mg/kg) in male mice. The data are compared on a per cent basis. p-Diethylaminoethyl diphenylpropylacetate (10 mg/kg ip) ( m ) was given 60 min prior to and iproniazide phosphate (100 mg/kg ip) (m) 30 min prior to the administration of barbiturates. Control animals received saline ( 5 ml/kg ip) (0).Each group consisted of ten animals.
-
80
-
60
-
n w
Y k
s h o w that inhibition of these enzyme systems potentiated the duration of equimolar doses of amobarbital and methylamobarbital. Comparison on a per ce,it basii shows that the response to amobarbital wai potentiated S and 14 times and methylamobarbital only 2 and 3 times. This is in line with the fact that the drugs which are metabolized a t a slower rate will be affected less if the activity of the inactivating enzyme(s) is altered, either inhibited or increased. These resulti can then be interpreted to indicate that methylamobarbital is metabolized to a lesser degree than amobarbital due to the fact that the preferential site of oxidation is blocked by methylation. The relative potericiei (in terms of .AD,o) of amobarbital, methylamobarbital, and butethal are shown in Figure 4. AIethylamobarbital is 1.h time:, as potent as butethal, whereas amobarbital is 1.3 times a5 potent as hutcthal when compared on an equimolar basis. I t can be said that the onset of action of barbiturates irelated to partition coefficientes since the potencies of methylamobarbital, amobarbital, and butethal increase (Figure 4) with increa-ing partition coefficients. However, when one looks a t duration of action (Figure l ) , butethal appears to be longer acting than amobarbital per unit dosage which is opposite to the potency relationqhip above. Rutethal may be longer acting
IO0
I
t; z
6
5
40-
u U W
20
-
1.60
1.60 LOG
1.76
1.84
1.92
2.00
D O S E OF B A R B I T U R A T E (MGJKG. I?)
Figure 4.--Log dose-response (onset of action) curves of amobarbital (AlIB.Na) ( C ) , butethal (BUT.Na) (O),and methylin male mice. Each point repreamobarbital (CH&IB) (0) sents the value obtained from ten animals. ADjo’s (anesthetic dose for .jO(y of the animals) in mmole were CHaAlIB, 0.185: AAIB, 0.240: BUT, 0.3:30.
than amobarbital because of its lower log P value and because it does not contain a tertiary w - 1 hydrogen. One can explain these results by correlating potency (onset of action) with the partition coefficient as shown in the p ~ i s t , ~whereas ,3 duration of action is more dependent upon the rate of metabolism and riot entirely on the partition coefficieiitq.
