Naunyn- Schmiedeberg's Arch Pharmacol (1991) 344: 500 - 504
Naunyn-Schmiedeberg's
002812989100175E
Archivesof
Pharmacology
© Springer-Verlag1991
Effect of cigarette smoke on pharmacokinetics of oral, intrarectal, or intravenous indomethacin in rats Toshiko Yoshida 1, Yutaka Gomita 2, and Ryozo Oishi 1 1Departments of Pharmacology and 2Hospital Pharmacy, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan Received February 25, 1991 / Accepted June 26, 1991
Summary. The effect of cigarette smoke exposure on the pharmacokinetics of indomethacin administered orally, intravenously or intrarectally was investigated in rats. When cirgarette smoke exposure was performed for 10 rain using a H a m b u r g II smoking machine immediately after the oral administration of indomethacin (5 mg/kg), the plasma indomethacin concentration was significantly lowered during the first 2 h after administration. However, there was no significant difference in plasm a indomethacin concentration between the cigarette smoke-exposed and nonexposed control rats thereafter. Cigarette smoke exposure caused a significant decrease in the area under the concentration-time curve from 0 to 4 h (AUC0_4) and a prolongation of the time to reach the m a x i m u m concentration (tmax). The plasma level of Odesmethyl-indomethacin (a major metabolite) was not significantly changed by cigarette smoke. When indomethacin (5 m g / k g ) was administered to rats intravenously or intrarectally, cigarette smoke exposure did not have any influence on the pharmacokinetics of indomethacin or 0-desmethyl-indomethacin. The pharmacokinetic effect of cigarette smoke on orally administered indomethacin was mimicked by the subcutaneous injection of nicotine at 0.3 m g / k g but not at 0.1 mg/kg. These results suggest that acute exposure to cigarette smoke decreases the plasma concentration of indomethacin when it is administered orally but not intrarectally or intravenously.
smoking facilitates the disposition of a variety of drugs in m a n (Jusko 1979), and the effects of drugs such as pentazocine (Keeri-Szanto and Pomeroy 1971), benzodiazepines (Jick 1974), and chlorpromazine (Swett 1974) are known to be reduced in smokers. Therefore, many studies concerning the effect of smoking on drugs disposition have been performed. However, little is known about the influence of tobacco smoking on drug pharmacokinetics for agents given rectally in the form of a suppository. Indomethacin (IM) is a non-steroidal anti-inflammatory agent that is often used as a rectal suppository to avoid gastrointestinal irritation. Although extensive studies have been performed on the pharmacokinetics of IM in conjunction with compounds affecting drug metabolism like cimetidine (Howes et al. 1983), phenylbutazone, and probenecid (Yesair et al. 1970b), there have been few works concerning the effect of smoking on IM. The tobacco smoke inhalation apparatus (Hamburg II smoking machine) has enabled the investigation of the effect of cigarette smoking on drug pharmacokinetics in small animals. Using this apparatus, we have previously examined the effect of smoking on the pharmacokinetics of nicorandil (Gomita et al. 1990a) and theophylline (Gomita et al. 1990b) in rats. The present study was designed to examine the effect of cigarette smoking on the pharmacokinetics of IM administered to rats orally, intravenously, or intrarectally.
Key words: Cigarette smoke - Suppository - Pharma-
Methods
cokinetics Indomethacin methacin - Nicotine
-
O-Desmethyl-indo-
Introduction Tobacco smoking is one of the factors that affect the pharmacokinetics of drugs. It has been reported that Send offprint requests to R. Oishi at the above address
We used male Wistar rats weighing 190-210 g (SeiwaExperimentalAnimals, Fukuoka, Japan). Groups of four or five animals werehoused together in stainless steel cages (35 × 23 x 20 cm), and food and water were given ad libitum except during the 24-h fasting period before the experiment. The animals were maintained on a 12-h light-dark cycle (light from 8.00 to 20.00h) at a room temperature of 22-24°C. For exposingthe rats to cigarette smoke, a Hamburg II smoking machine (Borgwaldt, Hamburg, FRG) was used. The apparatus consisted of a smoking head to which up to 30 cigarettes could be attached, a smoking channel, a smoking chamber slide piece, an inhalation chamber, and 10 animal holders for exposing small animals to cigarette
501 smoke. The smoke was mixed with air at a ratio of 1 : 7. After the first 15 cigarettes had burned out, the remaining 15 cigarettes were lighted. The puff duration was 2 sec and the puff frequency was 15 puffs/min (Gomita et al. 1990a). A commercially available brand of cigarette (Long Peace: Japan Tobacco Co., Tokyo, Japan) was used. When each cigarette is smoked until it is two-thirds gone using a smoking machine (inhalation volume: 35 ml; duration: 2 sec), 2.2 mg of r/icotine and 23 mg of tar are detected in the smoke. Immediately after the administration of IM, rats were exposed to cigarette smoke for 10 rain. Control rats were held in the same apparatus for 10 rain without smoke exposure. When examined the effect of subcutaneous administration of nicotine on the pharmacokinetics of oral IM, all rats were also held in the same apparatus for 10 min. At various times (0.25 - 24 h) after IM administration, 60 Ixl aliquots of blood were collected into heparinized capillary tubes from the tail vein under light local anesthesia with ethyl aminohenzoate ointment. Each blood sample was immediately centrifuged at 10000 rpm for 5 min and 20 gl of the plasma thus obtained was transferred to an Eppendorf tube containing 50 ng of butylparavene as an internal standard. After precipitating plasma protein by adding 60 gl of acetonitrile, the mixture was centrifuged at 10000 rpm for 20 min. The plasma IM and 0-desmethyMndomethacin (O-DM-IM, a major metabilite) concentrations were simultaneously determined using highperformance liquid chromatography (HPLC) with UV spectrophotometric detection. A 20%tl aliquot of the supernatant was directly injected into the HPLC system, which was composed of a pump (LC-6A, Shimadzu, Kyoto), a reverse phase column (Chemcopak 7C18 ODS-H, 4.0 × 250 mm, Chemco Scientific Co., Osaka), a Rheodyne sample injector (model 7125) and a recorder (model 561, Hitachi, Tokyo). The mobile phase was a mixture of 0.I% H3PO 4 and methanol (1 : 3, v/v), the flow rate was 1.4 ml/min, and the effluent was monitored at 254 nm. Pure IM and O-DM-IM were donated by Sumitomo Chemical Co. (Takarazuka, Japan). Polyethylenglycol 1000 and 4000 and carboxymethyl cellulose-Na were obtained from Nacalai Tesque Inc. (Kyoto, Japan), and (-)-nicotine ditartrate was obtained from Sigma Chemical Co. (St. Louis, MO, USA). Other chemicals used were of analytical or reagent grade. An IM suppository was prepared as follows: 5 mg of IM was dissolved in I g of polyethyleneglycol base (a mixture containing 75% polyethyleneglycol 1000 and 25% polyethyleneglycol 4000) at 60°C. The solution was immediately poured into the a polyethylene tube (0.5 mm inside diameter) and cooled at 4°C. After the solution had hardened, an end of the tube was cut off and the contents were pushed out from the other end. The suppositories produced in this manner were stored at 4°C and used within 3 days of preparation. When administered orally, 5 mg of IM was emulsified in 2 ml of 0.5O/o carboxymethyl cellulose-Na and was given at a dose of 5 mg/kg. When administered intrarectally, the IM suppository was cut to the size corresponding to a dose of 5 mg/kg and inserted into the rectum, and the anus was then closed with alkyl-a-cyanoacrylate monomer (Aron Alpha, Sankyo Co., Tokyo, Japan). For intravenous administration, IM was dissolved in a small quantity of 1 N NaOH and diluted to the final concentration of 5 mg/ml with 0.05 M phosphate buffer (pH 7.7) containing 5% ethanol. This IM solution was injected into the inguinal vein under light ether anesthesia at a dose of 5 mg/kg. Nicotine was dissolved in saline and was injected subcutaneously at doses of 0.1 and 0.3 mg base/kg immediately after IM administration. Pharmacokinetic parameters were obtained by multivariate (Yamaoka et al. 1981) and moment (Yamaoka et al. 1978) analyses. Statistical evaluation was performed using analysis of variance followed by Dunnett's test or a two-tailed Student's t-test.
Results
Effect of cigarette smoke on the plasma I M and O-DM-IM concentrations after oral I M The changes in plasma IM and O-DM-IM concentrations after the oral administration of IM are shown in Fig. 1 for control and cigarette smoke-exposed rats. The plasma IM
10
_=
g
K
O
v i
1 2
4
i
6
;
1~2 Time after IM administration (h)
i
24
11
Fig. 1. Time course of the changes in the plasma IM and O-DM-IM concentrations after the oral administration of IM (5 mg/kg) in the control (O) and cigarette smoke-exposed ( • ) groups. Each point represents the mean_+SEM for even rats. *P
Naunyn-Schmiedeberg's
002812989100175E
Archivesof
Pharmacology
© Springer-Verlag1991
Effect of cigarette smoke on pharmacokinetics of oral, intrarectal, or intravenous indomethacin in rats Toshiko Yoshida 1, Yutaka Gomita 2, and Ryozo Oishi 1 1Departments of Pharmacology and 2Hospital Pharmacy, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan Received February 25, 1991 / Accepted June 26, 1991
Summary. The effect of cigarette smoke exposure on the pharmacokinetics of indomethacin administered orally, intravenously or intrarectally was investigated in rats. When cirgarette smoke exposure was performed for 10 rain using a H a m b u r g II smoking machine immediately after the oral administration of indomethacin (5 mg/kg), the plasma indomethacin concentration was significantly lowered during the first 2 h after administration. However, there was no significant difference in plasm a indomethacin concentration between the cigarette smoke-exposed and nonexposed control rats thereafter. Cigarette smoke exposure caused a significant decrease in the area under the concentration-time curve from 0 to 4 h (AUC0_4) and a prolongation of the time to reach the m a x i m u m concentration (tmax). The plasma level of Odesmethyl-indomethacin (a major metabolite) was not significantly changed by cigarette smoke. When indomethacin (5 m g / k g ) was administered to rats intravenously or intrarectally, cigarette smoke exposure did not have any influence on the pharmacokinetics of indomethacin or 0-desmethyl-indomethacin. The pharmacokinetic effect of cigarette smoke on orally administered indomethacin was mimicked by the subcutaneous injection of nicotine at 0.3 m g / k g but not at 0.1 mg/kg. These results suggest that acute exposure to cigarette smoke decreases the plasma concentration of indomethacin when it is administered orally but not intrarectally or intravenously.
smoking facilitates the disposition of a variety of drugs in m a n (Jusko 1979), and the effects of drugs such as pentazocine (Keeri-Szanto and Pomeroy 1971), benzodiazepines (Jick 1974), and chlorpromazine (Swett 1974) are known to be reduced in smokers. Therefore, many studies concerning the effect of smoking on drugs disposition have been performed. However, little is known about the influence of tobacco smoking on drug pharmacokinetics for agents given rectally in the form of a suppository. Indomethacin (IM) is a non-steroidal anti-inflammatory agent that is often used as a rectal suppository to avoid gastrointestinal irritation. Although extensive studies have been performed on the pharmacokinetics of IM in conjunction with compounds affecting drug metabolism like cimetidine (Howes et al. 1983), phenylbutazone, and probenecid (Yesair et al. 1970b), there have been few works concerning the effect of smoking on IM. The tobacco smoke inhalation apparatus (Hamburg II smoking machine) has enabled the investigation of the effect of cigarette smoking on drug pharmacokinetics in small animals. Using this apparatus, we have previously examined the effect of smoking on the pharmacokinetics of nicorandil (Gomita et al. 1990a) and theophylline (Gomita et al. 1990b) in rats. The present study was designed to examine the effect of cigarette smoking on the pharmacokinetics of IM administered to rats orally, intravenously, or intrarectally.
Key words: Cigarette smoke - Suppository - Pharma-
Methods
cokinetics Indomethacin methacin - Nicotine
-
O-Desmethyl-indo-
Introduction Tobacco smoking is one of the factors that affect the pharmacokinetics of drugs. It has been reported that Send offprint requests to R. Oishi at the above address
We used male Wistar rats weighing 190-210 g (SeiwaExperimentalAnimals, Fukuoka, Japan). Groups of four or five animals werehoused together in stainless steel cages (35 × 23 x 20 cm), and food and water were given ad libitum except during the 24-h fasting period before the experiment. The animals were maintained on a 12-h light-dark cycle (light from 8.00 to 20.00h) at a room temperature of 22-24°C. For exposingthe rats to cigarette smoke, a Hamburg II smoking machine (Borgwaldt, Hamburg, FRG) was used. The apparatus consisted of a smoking head to which up to 30 cigarettes could be attached, a smoking channel, a smoking chamber slide piece, an inhalation chamber, and 10 animal holders for exposing small animals to cigarette
501 smoke. The smoke was mixed with air at a ratio of 1 : 7. After the first 15 cigarettes had burned out, the remaining 15 cigarettes were lighted. The puff duration was 2 sec and the puff frequency was 15 puffs/min (Gomita et al. 1990a). A commercially available brand of cigarette (Long Peace: Japan Tobacco Co., Tokyo, Japan) was used. When each cigarette is smoked until it is two-thirds gone using a smoking machine (inhalation volume: 35 ml; duration: 2 sec), 2.2 mg of r/icotine and 23 mg of tar are detected in the smoke. Immediately after the administration of IM, rats were exposed to cigarette smoke for 10 rain. Control rats were held in the same apparatus for 10 rain without smoke exposure. When examined the effect of subcutaneous administration of nicotine on the pharmacokinetics of oral IM, all rats were also held in the same apparatus for 10 min. At various times (0.25 - 24 h) after IM administration, 60 Ixl aliquots of blood were collected into heparinized capillary tubes from the tail vein under light local anesthesia with ethyl aminohenzoate ointment. Each blood sample was immediately centrifuged at 10000 rpm for 5 min and 20 gl of the plasma thus obtained was transferred to an Eppendorf tube containing 50 ng of butylparavene as an internal standard. After precipitating plasma protein by adding 60 gl of acetonitrile, the mixture was centrifuged at 10000 rpm for 20 min. The plasma IM and 0-desmethyMndomethacin (O-DM-IM, a major metabilite) concentrations were simultaneously determined using highperformance liquid chromatography (HPLC) with UV spectrophotometric detection. A 20%tl aliquot of the supernatant was directly injected into the HPLC system, which was composed of a pump (LC-6A, Shimadzu, Kyoto), a reverse phase column (Chemcopak 7C18 ODS-H, 4.0 × 250 mm, Chemco Scientific Co., Osaka), a Rheodyne sample injector (model 7125) and a recorder (model 561, Hitachi, Tokyo). The mobile phase was a mixture of 0.I% H3PO 4 and methanol (1 : 3, v/v), the flow rate was 1.4 ml/min, and the effluent was monitored at 254 nm. Pure IM and O-DM-IM were donated by Sumitomo Chemical Co. (Takarazuka, Japan). Polyethylenglycol 1000 and 4000 and carboxymethyl cellulose-Na were obtained from Nacalai Tesque Inc. (Kyoto, Japan), and (-)-nicotine ditartrate was obtained from Sigma Chemical Co. (St. Louis, MO, USA). Other chemicals used were of analytical or reagent grade. An IM suppository was prepared as follows: 5 mg of IM was dissolved in I g of polyethyleneglycol base (a mixture containing 75% polyethyleneglycol 1000 and 25% polyethyleneglycol 4000) at 60°C. The solution was immediately poured into the a polyethylene tube (0.5 mm inside diameter) and cooled at 4°C. After the solution had hardened, an end of the tube was cut off and the contents were pushed out from the other end. The suppositories produced in this manner were stored at 4°C and used within 3 days of preparation. When administered orally, 5 mg of IM was emulsified in 2 ml of 0.5O/o carboxymethyl cellulose-Na and was given at a dose of 5 mg/kg. When administered intrarectally, the IM suppository was cut to the size corresponding to a dose of 5 mg/kg and inserted into the rectum, and the anus was then closed with alkyl-a-cyanoacrylate monomer (Aron Alpha, Sankyo Co., Tokyo, Japan). For intravenous administration, IM was dissolved in a small quantity of 1 N NaOH and diluted to the final concentration of 5 mg/ml with 0.05 M phosphate buffer (pH 7.7) containing 5% ethanol. This IM solution was injected into the inguinal vein under light ether anesthesia at a dose of 5 mg/kg. Nicotine was dissolved in saline and was injected subcutaneously at doses of 0.1 and 0.3 mg base/kg immediately after IM administration. Pharmacokinetic parameters were obtained by multivariate (Yamaoka et al. 1981) and moment (Yamaoka et al. 1978) analyses. Statistical evaluation was performed using analysis of variance followed by Dunnett's test or a two-tailed Student's t-test.
Results
Effect of cigarette smoke on the plasma I M and O-DM-IM concentrations after oral I M The changes in plasma IM and O-DM-IM concentrations after the oral administration of IM are shown in Fig. 1 for control and cigarette smoke-exposed rats. The plasma IM
10
_=
g
K
O
v i
1 2
4
i
6
;
1~2 Time after IM administration (h)
i
24
11
Fig. 1. Time course of the changes in the plasma IM and O-DM-IM concentrations after the oral administration of IM (5 mg/kg) in the control (O) and cigarette smoke-exposed ( • ) groups. Each point represents the mean_+SEM for even rats. *P
