EUROPEAN JOURNAL OF DRUG METABOUSM AND PHARMACOKINETICS, 1992, Vol. 17, No.3, pp. 227-232
Pharmacokinetics of heptacaine, a novel potent local anaesthetic agent, after rectal administration to rats V. FABERovA,I, M.DURISovA2, T. TRNOVEC2 and D. DIVISovA3 1DrugResearch Institute, Modra, Czechoslovakia 2Institute ofExperimental Pharmacology, SlovakAcademy ofSciences, Bratislava, Czechoslovakia 3Faculty ofPharmacy, Comenius University, Bratislava, Czechoslovakia
Received for publication: March 1991
Keywords: Heptaeaine, local anaesthetics, pharmacokinetics, rectal administration, therapy of hemorrhoids
SUMMARY The pharmacokinetics of heptacaine, N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride, a new long-acting potent carbanilate type local anaesthetic, proposed for local anaesthesia in complex treatment of hemorrhoids, was studied following its rectal administration to rats in the form of cocoa butter suppositories. The heptacaine plasma concentration, 0.0083% of dose/ml, peaked at 90 min post administration and the maximum rate of its bioavailability, 0.19% of dose/min, assessed by deconvolution, occurred 38 min post administration. The plasma elimination half-life of heptacaine was 133 min and its biological availability of 52% was comparable to other agents of the class.
INTRODUCTION Local anaesthetics are currently used for a temporary relief of discomfort, pain, itching, burning and irritation in connection with symptomatic treatment of hemorrhoidal disease (I, 2). Benzocaine, lidocaine, cinchocaine and pramoxine are recommended as safe and effective local anaesthetics to be used externally, i.e. in the perianal region and the lower anal canal. A novel group of local anaesthetics, characterized by the -NHCOo-, the carbanilate, group, was synthesized and is being preclinically tested as a result of the systematic search for new local anaesthetics that respond better to requirements of clinical practice with Pleasesend reprintrequests to : Dr TomS! Trnovec, Institute of Experimental Pharmacology, Sciences, 842 16 Bratislava, Czechoslovakia
Slovak Academy Dubravska cesta
of 9.
respect to their physico-chemical properties, pharmacology and side-effects (3-5). Heptacaine, N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride (Fig. I), is a new potent representative of the carbanilate class of local anaesthetic agents (6, 7). Heptacaine was suggested for treatment of pain associated with vascular tumours of the rectal mucous membrane on account of its promising pharmacodynamic properties (8, 9). Due to its extremely high lipophilicity, heptacaine seems to be related to the long-acting local anaesthetics and due to its particular physico-chemical properties, its activity increases with decreasing pH in contrast to other currently used local anaesthetics (10). These properties indicate a long lasting anaesthetic action in inflamed tissue. It is evident in the light of data on absorption of drugs by the rectal route that a fraction of the topically applied local anaesthetic may become available in the
228
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
CI
Fig. 1 : Chemical structure of heptacaine
* indicates position of 14C label
systemic circulation and pharmacologically active in the body. As there are no data about rectal absorption of heptacaine, this study was performed to assess the rate and extent of bioavailability of heptacaine after its rectal administration to rats.
MATERIALS AND METHODS (Heptyl-l-[14C)) heptacaine (11) dissolved in ethanol, specific activity 4.4 GBqlg and 2.26 GBq/ml was used. The radiochemical purity of the product, 98%, was checked by TLC performed on Silufol UV2S4 (Kavalier, Votice, Czechoslovakia) silica gel plates using the solvent systems: toluene!chlorofonnl acetone!diethylamine (7:2:4:1) and toluene!dioxane! anunonia (15:4:1). Heptacaine hydrochloride was dissolved in a mixture of water (0.7 ml) and [14C]_ heptacaine stock solution (0.3 ml). The resulting solution was mixed with cocoa butter (30 g), melted at 3YC, and poured into the mould. The suppositories were administered rectally to male Wistar rats weighing 180-220 g under ether anaesthesia. Before the experiment, the animals were starved overnight but were given water freely. The expulsion of the suppository was prevented by gently clamping the anus by Pean's forceps for 15 min. The dose of heptacaine administered rectally was 2.25 mglkg. Groups of 6 rats were killed under ether anaesthesia 15, 30, 45, 60. 90. 120, 240, 300 and 360 min after administration by withdrawal of blood into a heparinized syringe. Another group of 6 rats was housed for 72 h in glass metabolic cages and urine and faeces were' collected daily. Organs and faeces from both groups were weighed and aliquots were homogenized in borate buffer pH 9.2 (1:5. w/v). A selective radiochemical procedure based on double extraction of the parent molecule from alkaline media into n-heptane was used for specific assay of
heptacaine in plasma, homogenates or urine (12). Aliquots of the organic phase were mixed with Bray's liquid scintillator (Spolana, Neratovice, Czechoslovakia). For determination of total 14C radioactivity, the samples of biological material were digested in 25% KOH in 20% ethanol (1:4, w/v) for 4 days and 0.2 ml aliquots of the digests were mixed with 15 ml of the liquid scintillator SLS 41 (Spolana). Samples were counted for radioactivity in a liquid scintillation counter Packard TriCarb 300 CD. The heptacaine plasma concentration-time data were approximated by a multi-exponential function using an HP-9830 A computer programme of nonlinear regression analysis (13). A standard method was used for calculation of the phannacokinetic parameters (14). Biological availability of heptacaine after rectal administration was calculated as F = AUCrectaIlAUCi.v., where AUCrectal and AUCi.v. are the areas under the plasma concentration-time curve following the rectal and i.v. mode of administration, respectively. The rate of bioavailability of heptacaine after rectal administration was calculated by analytical deconvolution (15). The heptacaine i.v, data necessary for calculation of the rate and extent of bioavailability were those obtained from our previous study (16).
RESULTS AND DISCUSSION The plasma concentration of heptacaine following rectal administration of suppositories containing this drug is shown in Figure 2. It can be seen that after administration of the suppositories, heptacaine is absorbed into the systemic circulation. A peak plasma level of 0.0083% doselml was attained 89.9 min post administration. The heptacaine plasma concentrationtime curve data were agllroximated by the function C(t) = P(I) • (e-P(2)t - e- (3)t). The following optimal
V. Faberovd et al., Heptacaine kinetics: rectally admin.
229
%of Dose/m' 0.1
0.01
O'001+---.----,---r------,-----t
o
120
240
360 min
Fig. 2 : Plasma concentration versus time profile of heptacaine (*) and of total 14C radioactivity (filled squares) after rectal administration of [14C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
parameter estimates ± SD were found for this function (r = 0.936): P(I) = 6.45 x 10-3 ± 4.18 x 10-4; P(2) = 2.63 x 10-3 ± 4.07 x 10-4; and P(3) = 0.08 ± 0.02. Accordingly, the pharmacokinetics of heptacaine in plasma after its rectal administration were approximated by a linear open one-compartment model with elimination from the central compartment For this model, the following parameter estimates were obtained: ke = 0.0052 min-I; ka = 0.0204 min-I; tin = 132.7 min; and F = 0.52 - where ke is the elimination rate constant, k a is the absorption rate constant, tin is the elimination half-life, and F is the bioavailability. Heptacaine after its absorption was rapidly metabolized as its metabolites appeared in plasma simultaneously with the parent drug. It can be seen that the time course of total 14C radioactivity in plasma paralleled that of the parent drug. The time course of heptacaine concentration in organs of the rat is depicted in Figure 3A. The time courses of heptacaine concentration in liver, kidney and spleen seem to be similar. The maximum level of heptacaine in these organs, about 0.05% of dose/g, was attained approximately 1-2 h after administration of the drug. The concentration of heptacaine in the lungs attained its peak earlier than in the liver, kidney or spleen. The lowest level of the druf. was seen in the heart. The time course of total 4C radioactivity in the organs is shown in Figure 3B. Of the organs studied, the total 14C radioactivity was the highest in the liver.
The data on total 14C radioactivity contained in the rectum are shown in Figure 4. It can be seen that the total radioactivity in the rectum decreases exponentially with time. This indicates a first order absorption process. Data on excretion of heptacaine and of its labelled metabolites are shown in Figure 5. The animals excreted 20.9% and 36.8% of 14C administered in urine and faeces, respectively, within 72 h. The percentage of unchanged drug excreted in faeces amounted to up to 18.8% (Fig. 5A). Data on the rate of heptacaine bioavailability in systemic circulation obtained by the deconvolution calculation are shown in Figure 6. The rate of heptacaine appearance in the systemic circulation peaked 38 min after administration, at which time about 0.19% of the dose administered entered the systemic circulation each minute. The prevailing pH in the rectum (7.5-8.0) and the physico-chemical properties of heptacaine (pKa = 8.87; partition coefficient = 5100 ± 540) are favourable for absorption of heptacaine after its rectal administration. It can be seen by comparison of the heptacaine plasma concentration-time curve (Fig. 2) with the heptacaine bioavailability rate curve (Fig. 6), that the maximum rate of heptacaine bioavailability occurred earlier (38 min) after heptacaine administration than its peak plasma concentration (90 min). It seems to be important for interpretation of
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
230
1.. of
Dose/g
A
~'-- +
0.1
1
~
~ ~+---=-r=-I ---T=~+=====H
t~+ t---I. -- 1-** ' -+ - __**1 I
I~+~
J. I
I
0.01 L-.--t----+----+----+----I----;L~I'
jI I
HEART
ER
KIDNEY
L.------t----+----+---1----1----::S~PLEEN - +_ _- t I-_ _-t------:::-!"':"----t------=-!I LUNGS I
__
0.0010-
120
240
360
min
;0 of
Dose/g
B
0.1
0.01
120
240
Fig. 3 : 0l},an concentration versus time profile of heptacaine (A) and of total 14C radioactivity (B) after rectal administration of C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
r'
V. Faberovd et al., Heptacaine kinetics: rectally admin.
231
A
1. of Dose
%of Dose/g
so
10
25
r------t OoJ------------------o 24 72 48
0.1 +---.-----.----,----.-----.--~ 360 240 120 o min
Fig. 4 : Concentration of heptacaine in the rectum versus time profile after rectal administration of . . . . to rats. [ 14C]-hep tacai ame containing suppositones Results are expressed as the mean ± SE of 6 experiments
h
B
i. of Dose 50
i. of Dose/min 0.2
25
...
...
0.1
0+----------------_
o
0-1---,...----,.------.--........- - - - , - - -....... 120 240 360 o
min Fig. 6 : The rate of bioavailability of heptacaine in systemic circulation after rectal administration of 4 C]-heptacaine containing suppositories to rats
e
the data obtained that the rate of availability of heptacaine reflects a composite process involving fusing of the suppository base at body temperature, the release of the drug and its passage through several anatomical structures of the gut wall into the capillary blood. In general, the systemic pharmacodynamic effects due to absorption of the locally acting drugs
24
48
72 h
Fig. 5 : Excretion of heptacaine (*) and total 14C radioactivity (filled squares) in the faces (A) and urine (B) after rectal administration of 4 C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
e
into circulating blood are not desirable. We have shown that bioavailability of heptacaine administered rectally is comparable to that of amide-type local anaesthetics (17. 18) used for anaesthesia in the anal area. It has been found that the systemic availability of heptacaine after rectal administration was greater than after oral administration. compare 36% versus 52% (16). This can be explained by the draining of some of the capillaries of the rectum into the systemic circulation.
232
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
REFERENCES 1. Danti A.G.• Talley JR (1985) : Hemorrhoidal disease and its treatment. Phann. Index, 7, 9-16. 2. Wienert V. (1984) : Situelle therapie des hamorrhoidalleidens. Therapiewoche, 34, 5244-5253. 3. Benes L., Tichy M, Svec P., Kozlovsk§ J., Stefek M., Borovanskj A. (1979): New basic carbanilates with local anaesthetic and antiarrltythmic activity. Eur. J. Med. Chem., 3, 283-284. 4. Benes L., Borovansk§ A., Koplioovli L. (1972) : Basische trans- und cis cyklohexy1ester substituirter alkoxycarbanilsiiuren. Arch. Phann., 305, 648-654. 5. Benes L., Borovansk§ A., Koplleovli L. (1969): Alkoxycarbanilic acid esters with high anaesthetic activity. Arzneimittelforschung, 19, 1902-1903. 6. C~:allirik J., Borovanskj A., Svec P. (1978): N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride, heptacaine, a new local anaesthetic. Pharmazie, 33, 297-298. 7. PeSlik M., Kopecky F., c~:ihlirik J., Borovansky A. (1980) : Study of local anestheticas. Part 70: Some physico-chemical properties of piperidinoethylesters of alkoxyphenylcarbamic acids. Pharmazie, 35, 150-152. 8. Svec P., Ci~lirilc J., Bederova E., Borovansky A. (1976): Study of local anesthetics. Pharmacological properties of
heptacaine. Acta Facultatis Pharmaceuticae, 29,81-83. 9. Kozlovskj J., 6~lirik J., Peslik M., Icnzinger F., Borovanskj A. (1982): Antiarrhythmic activity of heptacaine and some of its derivatives. Anneimittelforschung, 32, 1032-1036. 10. StoIc S., Stankovicova T. (1986): Effect oflocal anaesthetic and pH: new aspects. Drugs Exp. Clin., XII, 753-760. 11. Elbert T., Marko V., Filip J., Benes L. (1984) : Synthesis of 14 labelled heptacaine and carbisocaine, new local anaesthetic. J. Label. CompoRadiophann., 21, 101-109. 12. Sl!asnllr V., Benes L., Bezek S., Tmovec T. (1983): Extraction of the new local anesthetic heptacaine from biological material. Radiochem. Radioanal. Lett., 59, 45-52. 13. Kveton K. (1984): Nelinedmi regrese v jazyku basic. RegresnI programy v jazyku fortran a basic. Ed. CvUT, Praha, 14. Gibaldi M., Perrier D. (1982) : Pharmacokinetics. New York, Marcel Dekker. 15. Veng-Pedersen P. (1980) : An algorithm and computer program for deconvolution in linear pharmacokinetics. J. Pharmacokinet. Biopharm., 8, 463-481. 16. Sllasnllr V., Kllllay z, Bezek S., Tmovec T., DuriSovli M. (1987) : Pharmacokinetics of the new local anaesthetic N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride in rats and mice. Anneimittelforschung, 37,783-787. 17. DeBoer A.G., Breimer D.O., Pronk J., Gubbens-Stibbe J. (1980) : Rectal bioavailability of lidocaine in rats: Absence of significant first-pass elimination. J. Pharm. Sci., 69, 804-807. 18. DeBoer A.G., Breimer D.O., Mattie H., Pronk J., Gubbens-Stibbe J. (1979) : Rectal bioavailability of lidocaine in man. Pharmacol. Ther., 26, 701-709.
am.
Pharmacokinetics of heptacaine, a novel potent local anaesthetic agent, after rectal administration to rats V. FABERovA,I, M.DURISovA2, T. TRNOVEC2 and D. DIVISovA3 1DrugResearch Institute, Modra, Czechoslovakia 2Institute ofExperimental Pharmacology, SlovakAcademy ofSciences, Bratislava, Czechoslovakia 3Faculty ofPharmacy, Comenius University, Bratislava, Czechoslovakia
Received for publication: March 1991
Keywords: Heptaeaine, local anaesthetics, pharmacokinetics, rectal administration, therapy of hemorrhoids
SUMMARY The pharmacokinetics of heptacaine, N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride, a new long-acting potent carbanilate type local anaesthetic, proposed for local anaesthesia in complex treatment of hemorrhoids, was studied following its rectal administration to rats in the form of cocoa butter suppositories. The heptacaine plasma concentration, 0.0083% of dose/ml, peaked at 90 min post administration and the maximum rate of its bioavailability, 0.19% of dose/min, assessed by deconvolution, occurred 38 min post administration. The plasma elimination half-life of heptacaine was 133 min and its biological availability of 52% was comparable to other agents of the class.
INTRODUCTION Local anaesthetics are currently used for a temporary relief of discomfort, pain, itching, burning and irritation in connection with symptomatic treatment of hemorrhoidal disease (I, 2). Benzocaine, lidocaine, cinchocaine and pramoxine are recommended as safe and effective local anaesthetics to be used externally, i.e. in the perianal region and the lower anal canal. A novel group of local anaesthetics, characterized by the -NHCOo-, the carbanilate, group, was synthesized and is being preclinically tested as a result of the systematic search for new local anaesthetics that respond better to requirements of clinical practice with Pleasesend reprintrequests to : Dr TomS! Trnovec, Institute of Experimental Pharmacology, Sciences, 842 16 Bratislava, Czechoslovakia
Slovak Academy Dubravska cesta
of 9.
respect to their physico-chemical properties, pharmacology and side-effects (3-5). Heptacaine, N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride (Fig. I), is a new potent representative of the carbanilate class of local anaesthetic agents (6, 7). Heptacaine was suggested for treatment of pain associated with vascular tumours of the rectal mucous membrane on account of its promising pharmacodynamic properties (8, 9). Due to its extremely high lipophilicity, heptacaine seems to be related to the long-acting local anaesthetics and due to its particular physico-chemical properties, its activity increases with decreasing pH in contrast to other currently used local anaesthetics (10). These properties indicate a long lasting anaesthetic action in inflamed tissue. It is evident in the light of data on absorption of drugs by the rectal route that a fraction of the topically applied local anaesthetic may become available in the
228
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
CI
Fig. 1 : Chemical structure of heptacaine
* indicates position of 14C label
systemic circulation and pharmacologically active in the body. As there are no data about rectal absorption of heptacaine, this study was performed to assess the rate and extent of bioavailability of heptacaine after its rectal administration to rats.
MATERIALS AND METHODS (Heptyl-l-[14C)) heptacaine (11) dissolved in ethanol, specific activity 4.4 GBqlg and 2.26 GBq/ml was used. The radiochemical purity of the product, 98%, was checked by TLC performed on Silufol UV2S4 (Kavalier, Votice, Czechoslovakia) silica gel plates using the solvent systems: toluene!chlorofonnl acetone!diethylamine (7:2:4:1) and toluene!dioxane! anunonia (15:4:1). Heptacaine hydrochloride was dissolved in a mixture of water (0.7 ml) and [14C]_ heptacaine stock solution (0.3 ml). The resulting solution was mixed with cocoa butter (30 g), melted at 3YC, and poured into the mould. The suppositories were administered rectally to male Wistar rats weighing 180-220 g under ether anaesthesia. Before the experiment, the animals were starved overnight but were given water freely. The expulsion of the suppository was prevented by gently clamping the anus by Pean's forceps for 15 min. The dose of heptacaine administered rectally was 2.25 mglkg. Groups of 6 rats were killed under ether anaesthesia 15, 30, 45, 60. 90. 120, 240, 300 and 360 min after administration by withdrawal of blood into a heparinized syringe. Another group of 6 rats was housed for 72 h in glass metabolic cages and urine and faeces were' collected daily. Organs and faeces from both groups were weighed and aliquots were homogenized in borate buffer pH 9.2 (1:5. w/v). A selective radiochemical procedure based on double extraction of the parent molecule from alkaline media into n-heptane was used for specific assay of
heptacaine in plasma, homogenates or urine (12). Aliquots of the organic phase were mixed with Bray's liquid scintillator (Spolana, Neratovice, Czechoslovakia). For determination of total 14C radioactivity, the samples of biological material were digested in 25% KOH in 20% ethanol (1:4, w/v) for 4 days and 0.2 ml aliquots of the digests were mixed with 15 ml of the liquid scintillator SLS 41 (Spolana). Samples were counted for radioactivity in a liquid scintillation counter Packard TriCarb 300 CD. The heptacaine plasma concentration-time data were approximated by a multi-exponential function using an HP-9830 A computer programme of nonlinear regression analysis (13). A standard method was used for calculation of the phannacokinetic parameters (14). Biological availability of heptacaine after rectal administration was calculated as F = AUCrectaIlAUCi.v., where AUCrectal and AUCi.v. are the areas under the plasma concentration-time curve following the rectal and i.v. mode of administration, respectively. The rate of bioavailability of heptacaine after rectal administration was calculated by analytical deconvolution (15). The heptacaine i.v, data necessary for calculation of the rate and extent of bioavailability were those obtained from our previous study (16).
RESULTS AND DISCUSSION The plasma concentration of heptacaine following rectal administration of suppositories containing this drug is shown in Figure 2. It can be seen that after administration of the suppositories, heptacaine is absorbed into the systemic circulation. A peak plasma level of 0.0083% doselml was attained 89.9 min post administration. The heptacaine plasma concentrationtime curve data were agllroximated by the function C(t) = P(I) • (e-P(2)t - e- (3)t). The following optimal
V. Faberovd et al., Heptacaine kinetics: rectally admin.
229
%of Dose/m' 0.1
0.01
O'001+---.----,---r------,-----t
o
120
240
360 min
Fig. 2 : Plasma concentration versus time profile of heptacaine (*) and of total 14C radioactivity (filled squares) after rectal administration of [14C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
parameter estimates ± SD were found for this function (r = 0.936): P(I) = 6.45 x 10-3 ± 4.18 x 10-4; P(2) = 2.63 x 10-3 ± 4.07 x 10-4; and P(3) = 0.08 ± 0.02. Accordingly, the pharmacokinetics of heptacaine in plasma after its rectal administration were approximated by a linear open one-compartment model with elimination from the central compartment For this model, the following parameter estimates were obtained: ke = 0.0052 min-I; ka = 0.0204 min-I; tin = 132.7 min; and F = 0.52 - where ke is the elimination rate constant, k a is the absorption rate constant, tin is the elimination half-life, and F is the bioavailability. Heptacaine after its absorption was rapidly metabolized as its metabolites appeared in plasma simultaneously with the parent drug. It can be seen that the time course of total 14C radioactivity in plasma paralleled that of the parent drug. The time course of heptacaine concentration in organs of the rat is depicted in Figure 3A. The time courses of heptacaine concentration in liver, kidney and spleen seem to be similar. The maximum level of heptacaine in these organs, about 0.05% of dose/g, was attained approximately 1-2 h after administration of the drug. The concentration of heptacaine in the lungs attained its peak earlier than in the liver, kidney or spleen. The lowest level of the druf. was seen in the heart. The time course of total 4C radioactivity in the organs is shown in Figure 3B. Of the organs studied, the total 14C radioactivity was the highest in the liver.
The data on total 14C radioactivity contained in the rectum are shown in Figure 4. It can be seen that the total radioactivity in the rectum decreases exponentially with time. This indicates a first order absorption process. Data on excretion of heptacaine and of its labelled metabolites are shown in Figure 5. The animals excreted 20.9% and 36.8% of 14C administered in urine and faeces, respectively, within 72 h. The percentage of unchanged drug excreted in faeces amounted to up to 18.8% (Fig. 5A). Data on the rate of heptacaine bioavailability in systemic circulation obtained by the deconvolution calculation are shown in Figure 6. The rate of heptacaine appearance in the systemic circulation peaked 38 min after administration, at which time about 0.19% of the dose administered entered the systemic circulation each minute. The prevailing pH in the rectum (7.5-8.0) and the physico-chemical properties of heptacaine (pKa = 8.87; partition coefficient = 5100 ± 540) are favourable for absorption of heptacaine after its rectal administration. It can be seen by comparison of the heptacaine plasma concentration-time curve (Fig. 2) with the heptacaine bioavailability rate curve (Fig. 6), that the maximum rate of heptacaine bioavailability occurred earlier (38 min) after heptacaine administration than its peak plasma concentration (90 min). It seems to be important for interpretation of
Eur. J. DrugMetab. Pharmacokinet., 1992, No.3
230
1.. of
Dose/g
A
~'-- +
0.1
1
~
~ ~+---=-r=-I ---T=~+=====H
t~+ t---I. -- 1-** ' -+ - __**1 I
I~+~
J. I
I
0.01 L-.--t----+----+----+----I----;L~I'
jI I
HEART
ER
KIDNEY
L.------t----+----+---1----1----::S~PLEEN - +_ _- t I-_ _-t------:::-!"':"----t------=-!I LUNGS I
__
0.0010-
120
240
360
min
;0 of
Dose/g
B
0.1
0.01
120
240
Fig. 3 : 0l},an concentration versus time profile of heptacaine (A) and of total 14C radioactivity (B) after rectal administration of C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
r'
V. Faberovd et al., Heptacaine kinetics: rectally admin.
231
A
1. of Dose
%of Dose/g
so
10
25
r------t OoJ------------------o 24 72 48
0.1 +---.-----.----,----.-----.--~ 360 240 120 o min
Fig. 4 : Concentration of heptacaine in the rectum versus time profile after rectal administration of . . . . to rats. [ 14C]-hep tacai ame containing suppositones Results are expressed as the mean ± SE of 6 experiments
h
B
i. of Dose 50
i. of Dose/min 0.2
25
...
...
0.1
0+----------------_
o
0-1---,...----,.------.--........- - - - , - - -....... 120 240 360 o
min Fig. 6 : The rate of bioavailability of heptacaine in systemic circulation after rectal administration of 4 C]-heptacaine containing suppositories to rats
e
the data obtained that the rate of availability of heptacaine reflects a composite process involving fusing of the suppository base at body temperature, the release of the drug and its passage through several anatomical structures of the gut wall into the capillary blood. In general, the systemic pharmacodynamic effects due to absorption of the locally acting drugs
24
48
72 h
Fig. 5 : Excretion of heptacaine (*) and total 14C radioactivity (filled squares) in the faces (A) and urine (B) after rectal administration of 4 C]-heptacaine containing suppositories to rats. Results are expressed as the mean ± SE of 6 experiments
e
into circulating blood are not desirable. We have shown that bioavailability of heptacaine administered rectally is comparable to that of amide-type local anaesthetics (17. 18) used for anaesthesia in the anal area. It has been found that the systemic availability of heptacaine after rectal administration was greater than after oral administration. compare 36% versus 52% (16). This can be explained by the draining of some of the capillaries of the rectum into the systemic circulation.
232
Eur. J. Drug Metab. Pharmacokinet., 1992, No.3
REFERENCES 1. Danti A.G.• Talley JR (1985) : Hemorrhoidal disease and its treatment. Phann. Index, 7, 9-16. 2. Wienert V. (1984) : Situelle therapie des hamorrhoidalleidens. Therapiewoche, 34, 5244-5253. 3. Benes L., Tichy M, Svec P., Kozlovsk§ J., Stefek M., Borovanskj A. (1979): New basic carbanilates with local anaesthetic and antiarrltythmic activity. Eur. J. Med. Chem., 3, 283-284. 4. Benes L., Borovansk§ A., Koplioovli L. (1972) : Basische trans- und cis cyklohexy1ester substituirter alkoxycarbanilsiiuren. Arch. Phann., 305, 648-654. 5. Benes L., Borovansk§ A., Koplleovli L. (1969): Alkoxycarbanilic acid esters with high anaesthetic activity. Arzneimittelforschung, 19, 1902-1903. 6. C~:allirik J., Borovanskj A., Svec P. (1978): N-(2-(2-heptyloxyphenylcarbamoyloxy)ethyl)-piperidinium chloride, heptacaine, a new local anaesthetic. Pharmazie, 33, 297-298. 7. PeSlik M., Kopecky F., c~:ihlirik J., Borovansky A. (1980) : Study of local anestheticas. Part 70: Some physico-chemical properties of piperidinoethylesters of alkoxyphenylcarbamic acids. Pharmazie, 35, 150-152. 8. Svec P., Ci~lirilc J., Bederova E., Borovansky A. (1976): Study of local anesthetics. Pharmacological properties of
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