Europ.J.clin.Pharmacol. 8, 79-81 @ b y Springer-Verlag 1975

(197~

Acetylation of Procaine Amide in Man. A Preliminary Communication* E. Karlsson, G. ~berg, P. Collste, Lilian Molin, B. Norlander and F. SjSqvist Departments of Pharmacology, Clinical Pharmacology and Internal Medicine (Division of Cardiology) University of LinkSping, LinkSping, and Department of Clinical Pharmacology, Karolinska Institutet, Huddinge Hospital, Huddinge, Sweden

Received: April 21, 1974,

accepted: May 25, 1974

S~r4~naPy. The metabolism of procaine amide was studied in 41 cardiac patients who had achieved steady state plasma concentrations of the drug. Acetylated procaine amide accounted for 31 ± 12% (range 16 63%) of the overall urinary recovery of the drug and is therefore a main metabolite in man. Plasma levels of the metabolite were usually lower but sometimes exceeded those of the parent compound with variations between 1 and 15 ~g/ml. The metabolite had a weaker effect than procaine amide on the maximal electrical driving velocity of isolated atrial strips from guinea pig.

Key words. Procaine amide, N-acetylprocaine amide, plasma concentration, renal excretion, acetylator phenotype.

Twenty years after the kinetics of procaine amide were first studied (I), the drug has been reinvestigated in man with special emphasis on the clinical importance of inter-individual differences in plasma concentrations (2,3,4) and the formulation of sustained release tablets (5,6). Little attention has been paid recently to the metabolism of procaine amide, but from studies in four human subjects it was concluded that N-acetylprocaine amide was a major metabolite (7). Several investigations have shown that isoniazid, hydralazine and certain sulphonamides are acetylated in the liver by a common enzyme system and that the population consists of rapid and slow acetylators (8). The latter are more prone to develop side-effects while taking these drugs, such as the systemic lupus erythematosus-like syndrome (SLE) after hydralazine (9). Since a similar syndrome has been observed during procaine amide treatment (I0), we became interested in the quantitative aspects of its acetylation in man. Forty-one patients were studied who had suspected or proven acute myocardial infarction treated with procaine amide because of ventricular arrhythmias. Unchanged procaine amide and its

acetylated metabolite, N-acetylprocaine amide, were measured in plasma and 24 h urine specimens by spectrophotofluorimetry (2) and gas chromatography (using 4-amino-N-2-piperidinoethyl) benzamide as internal standard), respectively. All the patients had achieved steady-state plasma concentrations of procaine amide within the apparent therapeutic range (2) of 4-8 ~g/ml (daily doses of 2.5-3.5 g at 4 hourly intervals). The excretion of unchanged procaine amide, N-acetylprocaine amide, and their sum in 24 h urine specimens were 50 ± 38%, 23 ± 11% and

' Number of subjects 8 7 6. 543 2I" 5 10 !5 20 25 30 35 40 45 50 55 60 65 Urinary N-czcetylprocaine amide in per cent of recovered procnine amide and N-Gcety[procaine omide

~Discussed in preliminary form at the AmericaSwedish workshop on clinical pharmacology at N.I.H. Bethesda, Maryland, USA, January 1973.

Fig. I. N-acetylprocaine amide in urine (24 hours) in per cent of recovered procaine amide and N-acetylprocaine amide (n = 41). Steady state conditions.

8O Table I. Maximal electrical driving velocity (concentrations/sec) before and at different times after adding drug (mean values ± SEM)

Procaine am±de

Acetylprocaine am±de

a = p < 0,05

Conc g/ml

n

before

5 min

I0 min

15 min

20 min

IxlO -5

6

7.8±0.2

7.8±0.2

7.8±0.2

7.7±0.2

7.5±0.2 a

5xlO -5

6

8.3±0.2

7.8±0.2 b

7.3±0.2 c

6.8±0.2 c

6.3±O.3 c

IxlO -4

6

7.3±0.3

5.8±0.3 c

5.2±O.2 c

4.9±0.3 c

4.8±0.3 c

5xlO -4

6

6.8±0.3

4.5±(n=2) 3.3±(n=2)

IxlO -3

6

7.0±0.6

4.5±(n=I) . . . . . . . . .

IxlO -5

6

7.9±0.5

7.9±0.5

7.8±0.4

7.8±0.5

7.7±O.5

5xlO -5

6

7.2±O.3

6.8±0.4 a

6.7±O.9 a

6.7±0.5 a

6.5±0.4 b

ixlO -4

6

7.7±0.7

7.0±0.9

7.0±0.6 a

6.8±0.4 b

6.5±0.4 b

5xlO -4

6

7.3±0.6

6.3±O.5 a

6.3±O.4 b

6.0±0.4 b

5.5±O.4 c

IxlO -3

6

7.7±O.3

6.4±0.4 c

5.8±0.4 c

5.8±0.4 c

5.7±0.3 c

b = p < 0,01

. . . . . .

c = p < 0,001

74 J 20% (mean ± SD) of the administered doses, respectively. Of the total amounts of procaine am±de and N-acetylprocaine am±de recovered in urine, unchanged procaine amine accounted for 69 ! 12% and N-acetylprocaine am±de for 31 ± 12% (range 16-63%). Thus, there was a marked interindividual variation in the degree of acetylation of procaine am±de. A plot of the renal excretion of N-acetylprocaine am±de in per cent of the administered dose of procaine am±de gave no evidence of a bimodal distribution. However, bimodality might be masked by considerable inter-individual variation in the absorption of procaine am±de (2). The urinary N-acetylprocaine am±de, as a percentage of the total procaine am±de and N-acetylprocaine am±de recovered, has been plotted as a histogram in Fig.l. In nine patients it was possible subsequently to study the plasma half-life of oral INH (I0 mg/ kg). If the ant±mode of plasma half-lives of INH distinguishing rapid and slow acetylators is set at 2.1 h (ii), then all patients with urinary N-acetylprocaine am±de below 20% belonged to the latter group and vice versa. These results show that acetylprocaine am±de is a major metabolite of procaine am±de in man. Plasma levels of the metabolite were usually lower but sometimes exceeded those of the parent compound with variations between 1 and 15 ~g/ml, the higher levels being seen in patients with impaired kidney function. Because of this finding, isolated strips from guinea-pig atria were incubated with procaine am±de or its acetylated metabolite in modified Ringer solution at 36 ° C, and drug effects evaluated as changes in maximal electrical driving rate (12). Table 1 shows that a significant effect

was found for both compounds at a concentration of 5"10 -5 g/ml. It would be of considerable interest to study the possible antiarrhythmic effect of N-acetylprocaine am±de in relation to its side-effects in man. Further studies in human volunteers with normal kidney function are required to establish whether the acetylation of procaine am±de and INH are mediated by the same enzyme system. After submitting this paper Drayer et al. (Proc. Soc. exp. Biol. Med. 146, 358-363, 1974) have reported antiarrhythmic properties of N-acetylprocaine am±de in animals. Elson et al. (Clin. Pharmacol. Ther. 15, 204, 1974) have mentioned in abstract form the presence of N-acetylprocaine am±de in the same concentration range as above in patients treated with procaineamide

References i. Mark, L.C., Kayden, H.J., Steele, J.M., Cooper, J.R., Berlin, I., Rowenstine, E.A., Brodie, B.B.: The physiological disposition and cardiac effect of procaine am±de. J. Pharmacol. exp. Ther. 702j 5-15 (1951) 2. Koch-Weser, J., Klein, S.W.: Procaine am±de dosage schedules, plasma concentrations and clinical effects. J. Amer.med.Ass. 215, 14541460 (1971) 3. Weily, H.S., Genton, E.: Pharmacokinetics of procainamide. Arch. intern. Med. 130, 366-369 (1972) 4. Collste, P., Karlsson, E.: Arrhythmia prophylaxis with procaine am±de: plasma concentrations

8!

5.

6.

7.

8.

9.

in relation to dose. Acta med.scand. 194, 405411 (1973) Karlsson, E.: Plasma levels of procaine amide after administration of conventional and sustained-release tablets. Europ, J. clin. Pharmacol. 6, 245-250 (1973) Fremstad, D., Dahl, S., Jacobsen, S., Lunde, P.K.M., Nadland, K.J., Marthinsen, A.A., Waaler, T., Landmark, K.H.: A new sustainedrelease tablet formation of procainamide. Europ. J. clin. Pharmacol. 6, 251-255 (1973) Dreyfuss, J., Bigger, J.T.H. Jr., Cohen, A.I., Schreiber, E°C.: Metabolism of procainamide in rhesus monkey and man. Clin. Pharmacol. Ther.13, 366-371 (1972) Evans, D.A.P.: Genetic variations in the acetylation of isoniazid and other drugs. Ann. N.Y. Acad. Sci. 151, 723-733 (1968) Perry, H.M. Jr.: Late toxicity to hydralazine resembling systemic lupus erythematosus or

Note Added in Proof After submitting this paper Drayer et al. (Proc. Soe. exp. Biol. Med. 146, 358-363, ]974) have reported antiarrhythmic properties of N-acetylprocaine amide in animals.

rheumatoid arthritis. Am. J. Med. 54, 58-72 (1973) lO.Dubois, E.L.: Procainamide induction of a systemic lupus erythematosus-like syndrome. Medicine (Baltimore) 48, 217-228 (1969) 11.Hanngren, A., Borg~, 0., SjSqvist, F.: Inactivation of isoniazid (INH) in Swedish tuberculous patients before and during treatment with paraaminosalicylic acid (PAS). Scand. J. resp. Dis. 51, 61-69 (1970) 12.Williams, E.M.V., Szekeres, L.: A comparison of tests for antifibrillatory action. Brit. J. Pharmacol. 17, 424-432 (1961) Dr. E. Karlsson Depts of Clinical Pharmacology and Internal Medicine (Division of Cardiology) Univ. of LinkSping S-581 85 LinkSping, Sweden

Elson et al. (Clin. Pharmacol. Then 15, 204, |974) have mentioned in abstract form the presence of N-acetylprocaine amide in the same concentration range as above in patients with procaine amide.

Acetylation of procaine amide in man. A preliminary communication.

The metabolism of procaine amide was studied in 41 cardiac patients who had achieved steady state plasma concentrations of the drug. Acetylated procai...
267KB Sizes 0 Downloads 0 Views