Effect of Methotrexate on Drug Absorption from the Rat Small Intestine in Situ and in Vitro

Abstract The effect of methotrexate (20 mg/kg intramuscularly) on the absorption of phenobarbitone, sulphafurazole, mecamylamine, quinidine and isoniazid from the rat small intestine was studied in situ and in vitro. The disappearance of all drugs studied from the intestinal fluid in situ was retarded on the third day after methotrexate administration. The fluid transfer and the amount of drugs passed through the intestinal wall in vitro were also decreased. The absorption of phenobarbitone was reversible within six days, whereas the absorption of quinidine was still retarded on the sixth day after methotrexate administration. Methotrexate did not modify the amount of quinidine excreted into the intestinal lumen after intravenous administration. The levels of other drugs except isoniazid in the blood at the end of the experiment showed changes corresponding to their disappearance from the intestinal lumen. In situ the drug levels in the intestinal wall were much lower than in vitro. Their levels in the intestinal wall reflected drug absorption in vitro but not in situ. The methotrexate-induced reversible decrease in absorption seems to be attributable at least partly to diminished water flux through the intestinal wall, although other mechanisms may also exist.     

Drug absorption from the irradiated rat small intestine in situ.

The absorption of acidic drugs phenobarbitone and sulphafurazole, basic drugs mecamylamine and quinidine, and a neutral drug isoniazid was studied in situ. Rats were irradiated 750 rad whole-body with 60Co and the absorption experiment was done three and six days thereafter using the cannulated small intestine of urethane-anaesthetized rats. Drug disappearance from the intestinal lumen and drug levels in the whole blood and intestinal wall were measured. In control rats phenobarbitone showed the most rapid absorption and mecamylamine the slowest. Irradiation retarded the disappearance of all drugs from the intestinal lumen on the third postirradiation day. Fluid absorption was also diminished. On the sixth postirradiation day the absorption of phenobarbitone, sulphafurazole and mecamylamine had returned to the control level, but the absorption of quinidine and isoniazid was still retarded. After i.v. administration of drugs they were not significantly excreted into the intestinal contents and irradiation did not modify excretion. The distribution of drugs between the intestinal fluid and the intestinal wall was complete in the first 10 min of experiment. Mecamylamine and quinidine were lowered in the whole blood by irradiation. Blood levels of drugs did not correlate well to the rate of disappearance of drugs from the intestinal lumen. The reversible changes in absorption induced by irradiation are probably secondary effects of irradiation on intestinal morphology, permeability and transport capacity, composition, and possibly blood flow.     

Absorption of morphine, butylscopolamine, mecamylamine and phenobarbitone from the small intestine of the triparanol-treated rat in situ.

The absorption of three basic drugs (morphine, butylscopolamine and mecamylamine) and an acidic drug (phenobarbitone) from the rat small intestine in situ was investigated by using a single perfusion technique. The effect of intestinal damage on absorption was studied by treating rats with triparanol 25-50 mg/kg every 24 h for three weeks. Treatment with triparanol decreased the cholesterol concentration in the intestinal wall. The absorption of morphine and mecamylamine was increased by treatment with triparanol, whereas the absorption of butylscopolamine was decreased and that of phenobarbitone remained unaltered. Treatment with triparanol decreased the concentration of mecamylamine in the intestinal wall, but the concentrations of other drugs were unchanged. When comparing the present in situ and previous in vitro results the decreased absorption of butylscopolamine after triparanol in situ was opposite to the finding in vitro. The increased absorption of morphine and unaltered absorption of phenobarbitone were in accordance with the finding in vitro. In situ the absorption of mecamylamine was increased, although in vitro it was unchanged. The structural damage, differences in composition of the intestinal wall and intestinal blood flow are supposed to be the reasons for changes in absorption.     

Effect of Colchicine on Drug Absorption from the Rat Small Intestine in Situ and in Vitro

Abstract The effect of colchicine (1 mg/kg intraperitoneally on two successive days) on the absorption of isoniazid, quinidine and sulphafurazole (sulfisoxazole) from the rat small intestine was studied in situ and in vitro. Colchicine produced two different types of histological damage in the small intestine, one with degenerative and the other with regenerative changes predominating. The small intestinal surface area was variably reduced. The colchicine-treated rats were lethargic and hypothermic as compared to controls. Colchicine retarded the disappearance of fluid and all three drugs from the small intestinal lumen in situ 2 days after the first colchicine injection. In vitro the total amounts of fluid and drugs passed through the intestinal wall were not significantly changed by colchicine, although there was a slight tendency towards an increased absorption of quinidine. Hence, colchicine as an antimitotic drug decreases drug absorption from the rat small intestine in situ, apparently due to the decreased surface area of the small intestine, the decreased water flux through the intestinal wall, the retarded intestinal motility and hypothermia of the rats. In vitro the changes are small, which makes the in vitro tests less suitable for studying the effect of colchicine on absorption.     

Drug absorption from in situ rat small intestine during metoclopramide administration.

The effect of metoclopramide on the absorption of drugs in solution in the small intestinal lumen of rats in situ was studied. Metoclopramide in doses up to 50 mg/kg sc did not significantly modify the disappearance of isoniazid and quinidine from the small intestinal lumen. At the end of the absorption experiments, quinidine in the whole blood of the experimental animals was increased after metoclopramide. The blood level did not correlate to the drug disappearance from the intestinal lumen. The results probably differ from those obtained when drugs are given orally to subjects treated with metoclopramide.     

Comparison of intestinal and peritoneal dialysis of theophylline and phenobarbitone in rats

Intestinal dialysis of drugs by oral administration of activated charcoal has been compared with peritoneal dialysis in rats. The average amounts of theophylline transported over 120 min into the intestinal lumen and the peritoneal cavity were 15.7 and 16.5% of the intravenous dose (10 mg kg-1), respectively, showing no significant difference, whereas the amount of the same intravenous dose of phenobarbitone transported from the blood into the intestinal lumen (7.8%) was significantly smaller than that entering the peritoneal cavity (12.5%). The net water flux showed that secretion predominated in the peritoneal transport whilst absorption predominated in the intestinal transport for both drugs. However, the net water flux in the intestinal lumen after intravenous theophylline (as aminophylline) was significantly smaller than that following phenobarbitone. The differences in transport across the two membranes could be due to differences in the intrinsic properties of the could be due to differences in the intrinsic properties of the membranes, such as the surface area, the thickness of the membrane and the distribution of blood vessels. Differences could also be due to differences in the pharmacological effects of the drugs.     

Effect of Ethanol and pH on the Adsorption of Drugs to Activated Charcoal: Studies in Vitro and in Man

Abstract: The effect of ethanol on the adsorption of aspirin, quinidine and amitriptyline to activated charcoal was studied in vitro at pH 1.2 and 7.0. The adsorption of these drugs was greatly dependent on the charcoal-drug ratio and on the pH. Ethanol (10%) significantly (P<0.001) increased the percentage of their unadsorbed fraction at both pHs in vitro. In six healthy volunteers activated charcoal (50 g), ingested 5 min. after aspirin (1000 mg) and quinidine sulfate (200 mg), reduced their bioavailability by about 70% (aspirin) and 99% (quinidine). A significant desorption of aspirin but not that of quinidine from charcoal was obvious on the second and third days and seemed to be related to the effect of pH. The absorption of ethanol was not significantly prevented by charcoal. The concomitant ingestion of alcohol (50 g) with drugs antagonized only slightly the ability of charcoal to reduce the absorption of aspirin and quinidine.     

Active Secretion of Drugs from the Small Intestinal Epithelium in Rats by P-Glycoprotein Functioning as an Absorption Barrier

Because the significance of P-glycoprotein in the in-vivo secretion of β-blockers in intestinal epithelial cells is unclear, the secretory mechanism for β-blockers and other drugs has been evaluated. Uptake of the β-blockers acebutolol, celiprolol, nadolol and timolol, and the antiarrhythmic agent, quinidine by the multidrug-resistant leukaemic cell line variant K562/ADM was significantly lower than that by drug-sensitive K562 cells, suggesting that these β-blockers are transported by P-glycoprotein out of cells. The reduced uptake of acebutolol by the drug-resistant K562/ADM cells was reversed by treating the cells with anti-P-glycoprotein monoclonal antibody, MRK16, whereas no such alteration in uptake was observed for drug-sensitive K562 cells. Acebutolol uptake by K562/ADM cells was, moreover, markedly enhanced, in a concentration-dependent manner, in the presence of the specific P-glycoprotein inhibitors, MS-209 and cyclosporin. Caco-2 cells were used for evaluation of the role of P-glycoprotein in intestinal permeability to drugs in-vitro. Basolateral-to-apical transport of acebutolol was twice that in the reverse direction. A similar polarized flux was also observed in the transport of vinblastine, but not in that of acetamide or mannitol. When in-vivo intestinal absorption was evaluated by the rat jejunal loop method, with simultaneous intravenous administration of a P-glycoprotein inhibitor, cyclosporin, intestinal absorption of both acebutolol and vinblastine increased 2.6- and 2.2-fold, respectively, but no such enhancement was observed in the absorption of acetamide. The effect of cyclosporin on the intestinal absorption of several drugs was further examined, and the extent of the contribution of P-glycoprotein as an absorption barrier to those drugs was evaluated. ATP depletion by occlusion of the superior mesenteric artery resulted in a clear increase in epithelial permeability to vinblastine, but not to 3-O-methylglucose or acetamide, indicating that vinblastine is secreted by ATP-dependent P-glycoprotein into the lumen. These findings demonstrate that P-glycoprotein plays a role as an absorption barrier by transporting several drugs from intestinal cells into the lumen.     

Characterization of intestinal absorption of quinidine, a P-glycoprotein substrate, given as a powder in rats

The characteristics of intestinal absorption of quinidine, a P-glycoprotein (P-gp) substrate in biopharmaceutics classification system (BCS) Class I, after oral administration as a powder in No. 9 HPMC capsule (diameter 2.6 mm; length 8.4 mm, volume 25 microl) was examined in rats from the following viewpoints: (i) main absorption site of quinidine, (ii) effect of dosage amounts (or luminal concentrations) of quinidine (10 mg vs 0.1 mg/kg), (iii) contribution of P-gp in quinidine absorption (0.1 mg/kg), and (iv) effect of gastric pH on quinidine absorption. Quinidine administered orally at a dose of 10 mg/kg was discharged from the stomach steadily with time and disappeared rapidly from the proximal intestine, where P-gp expression was low. In contrast, quinidine administered at a dose of 0.1 mg/kg remained longer in the gastrointestinal lumen than that administered at a dose of 10 mg/kg. The pretreatment with cyclosporine A, a P-gp inhibitor, greatly increased the intestinal absorption of quinidine given at a dose of 0.1 mg/kg. The gastric pH in untreated control rats was pH 3.6, and the treatment with ranitidine (10mg/kg, ip), a H2 blocker, increased to pH 6.4. The recovered amounts of quinidine 30 min after administration were 21.1% of dose in control rats and 94.7% in ranitidine-treated rats. The value of plasma AUC(0-6h) of quinidine in ranitidine-treated rats was about 40% that in untreated control rats. In conclusion, quinidine was rapidly and efficiently absorbed at the proximal intestine under ordinary circumstances. However, the oral bioavailability was modulated by various factors including the dose (or luminal concentration at the absorption site), presence of P-gp inhibitors, and gastrointestinal pH.     

Drug elimination function of rat small intestine: metabolism and intraluminal excretion

The metabolic and excretory function of the small intestine was investigated after oral and intravenous administration of drugs having an aromatic amino group to rats. After administration of drugs into the intestinal loop at the initial concentration of 0.1 mM, significant excretion of their N-acetylated forms into the lumen was observed. The amount of N-acetyl forms excreted in the lumen were 39.3 +/- 3.5, 63.5 +/- 20.9 and 18.0 +/- 13.8% of disappeared drugs from the lumen for p-aminobenzoic acid (PABA), p-aminosalicylic acid and sulfanilic acid, respectively. The excretion of p-acetamidobenzoic acid (Ac-PABA) after the absorption of PABA was reduced by the coadministration with salicylic acid, benzoic acid and 2,4-dinitrophenol. Salicylic acid noncompetitively inhibited the acetylation of PABA by the intestinal N-acetyltransferase. A good correlation was found between the intestinal N-acetyltransferase activities for drugs and the intraluminal excretion of N-acetyl derivatives after intestinal absorption of drugs. These results indicate that a drug having a higher susceptibility to intestinal N-acetyltransferase would undergo a greater excretion into the lumen in its N-acetyl form after intestinal absorption. After intravenous administration of PABA at a dose of 100 mumole/kg, 4.02 +/- 0.51% of dose was excreted in the lumen as Ac-PABA in 30 min. On the other hand, a significantly smaller fraction (2.72 +/- 0.68% of dose) was excreted in the lumen after intravenous injection of 100 mumole/kg of Ac-PABA. The larger excretion of Ac-PABA after administration of PABA indicates the contribution of intestinal metabolism on the transfer of PABA not only after oral, but also after intravenous administration.     

Absorption,Distribution and Metabolism of Sulphafurazole and Chloramphenicol in Rats with Intestinal Occlusion

Abstract The rat small intestine was occluded at the ileocaecal junction, while control rats underwent sham–operation. 42–46 hours later sulphafurazole 50 mg/kg or chloramphenicol 250 mg/kg was given by gavage. The drug concentrations in the whole blood, small intestine, large intestine, liver, kidneys, lungs and heart at respectively 30 and 60 min. after sulphafurazole and at 60 min. after chloramphenicol administration were assayed chemically. Occlusion increased the absolute liver and small intestinal weights. The total sulphafurazole levels reached in blood and other tissues except the large intestine at 30 min. were about similar at 60 min. both in sham–operated and occlusion rats, but occlusion increased total sulphafurazole in the large intestine at 60 min. Occlusion increased acetyl sulphafurazole in the liver, kidneys and lungs at 60 min. and in the large intestine acetyl sulphafurazole was higher at 60 min. (about 60 %) than at 30 min. (about 30 %) in both sham–operated and occlusion rats. Occlusion did not significantly modify total chloramphenicol in any tissue or blood. Occlusion increased free and NO₂–reduced chloramphenicol in the large intestine. It seems that occlusion does not alter the absorption or distribution of sulphafurazole and chloramphenicol, but modifies their inactivation by increasing metabolism and probably by altering their excretion through the large intestine.     

Concentration-dependent exsorption of quinidine in the rat intestine.

During intravenous infusion, the luminal concentration of quinidine was higher than the plasma concentration. The intestinal clearance (CLi) of the drug was measured by dividing the rate of appearance of the drug in the intestinal luminal perfusate by the plasma concentration. The CLi of quinidine was therefore much higher than the rate of luminal perfusion. Over the infusion dose range of 0.1-2 mg h-1, the CLi of quinidine decreased with increasing plasma concentration of quinidine. Adding quinidine into the luminal perfusate had little effect on the CLi of quinidine. Co-administration of quinidine with other agents intravenously did not alter the CLi of salicylic acid and urea, while the same treatment decreased the CLi of theophylline and S-disopyramide. In-vitro experiments on brush-border membrane vesicles showed that quinidine decreased the rate of Na+ uptake and H+ efflux. The inhibition was significant at quinidine concentrations above 20 microM. Quinidine was a more potent inhibitor than amiloride. At quinidine infusion rates less than 2 mg h-1, quinidine concentration in plasma or in the luminal perfusate was at the lower limit of the inhibitory concentration. Microclimate pH at the intestinal surface was also measured. At mid-jejunum, the microclimate pH increased 0.3 pH units by infusing 2 mg h-1 of quinidine, while the microclimate pH at most other measuring sites was not significantly altered by quinidine infusion. It was concluded that quinidine is exsorbed from blood into the intestinal lumen by a carrier-mediated pathway in addition to the passive diffusion. At high plasma concentration, quinidine exsorption becomes saturated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of gastrointestinal absorption of digoxin involving influx and efflux transporter in rats: application of mdr1a knockout (−/−) rats into absorption study of multiple transporter substrate

Abstract

1.?This study was aimed to characterize gastrointestinal absorption of digoxin using wild-type (WT) and multidrug resistance protein 1a [mdr1a; P-glycoprotein (P-gp)] knockout (?/?) rats.

2.?In WT rats, the area under the plasma concentration–time curve (AUC) of oral digoxin increased after oral pretreatment with quinidine at 30?mg/kg compared with non-treatment, but the increasing ratio tended to decrease at a high dose of 100?mg/kg. In mdr1a (?/?) rats, however, quinidine pretreatment caused a dose-dependent decrease in the AUC.

3.?Quinidine pretreatment did not alter the hepatic availability of digoxin, indicating that the changes in the digoxin AUC were attributable to inhibition of the absorption process by quinidine; i.e. inhibition of influx by quinidine in mdr1a (?/?) rats and inhibition of efflux and influx by quinidine in WT rats.

4.?An in situ rat intestinal closed loop study using naringin implied that organic anion transporting peptide (Oatp) 1a5 may be a responsible transporter in the absorption of digoxin.

5.?These findings imply that the rat absorption behavior of digoxin is possibly governed by Oatp1a5-mediated influx and P-gp-mediated efflux. The mdr1a (?/?) rat is therefore a useful in vivo tool to investigate drug absorption associated with multiple transporters including P-gp.     

Drug Liposome Partitioning as a Tool for the Prediction of Human Passive Intestinal Absorption

Purpose. Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development. Methods. Liposome distribution coefficients measured titrimetrically and solubility data at pH 6.8 were used to characterize 21 structurally diverse ionizable drugs covering a range from <5% to almost complete absorption. Results. A sigmoidal relationship was found between the percentage of human passive intestinal absorption and a new absorption potential parameter calculated from liposome distribution data and the solubility dose ratio. In contrast, the human absorption data did not correlate with an octanol-based absorption potential or partitioning data alone. Poor correlations were found between liposome and octanol partitioning of ionic species or nonionic bases indicating the profound differences of the partitioning systems. Conclusions. Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans. Profound differences between liposome and octanol partitioning were found for a highly diverse set of species. This titration technique may serve to generate liposome partitioning data for the selection and optimization of lead compounds and in drug development.     

Gastrointestinal absorption of quinidine from some solutions and commercial tablets

The gastrointestinal absorption of quinidine from three commercially available tablet products has been compared to that from a quinidine sulfate solution previously found to have 70% of the systematic availability of an intravenous dose. Quinidine gluconate solution was included in the study to compare the absorption characteristics of the two quinidine salts. The tablets were given in a counterbalanced sequence preceded by one quinidine solution and followed by the other in a crossover design. The three tablets proved to be equivalent to one another with respect to extent and rate of absorption. The absorption properties of the two solutions were indistinguishable. The tablets were equivalent to the solutions in extent but not in rate of absorption.     

Investigations on the biotransformation of mebendazole using an isolated perfused rat gut system

1. The intestinal metabolism of the benzimidazole, mebendazole (MEB), has been investigated using isolated perfused jejunal segments of rats. Significant absorption and intestinal metabolism of the substance was observed.

2. The metabolites, the reduced α-hydroxy-analogue, its glucuronide, and the decarbamoylated 2-amino-analogue, were transported into the resorbate collected at the serosal side or were resecreted into the gut lumen.

3. The intestinal decarbamoylation of mebendazole increased up to 20-fold after pretreatment with 3-methylcholanthrene (MC), and complete re-secretion of this metabolite into the gut lumen led to a total loss of the absorption of mebendazole and metabolites across the gut wall.

4. The results indicate the ability of the gut to metabolize mebendazole by phase I and II reactions.

5. An almost complete loss of bioavailability after induction of the gut enzyme system by MC was observed.     

The Role of the Gut Flora in the Metabolism of Prontosil and Neoprontosil in the Rat

1. The urinary excretion of total sulphanilamide (free and acetylated) in rats receiving Prontosil or Neoprontosil orally is considerably reduced when the rats are treated with antibiotics to suppress their intestinal flora. The absorption and metabolism of sulphanilamide are unaffected by such treatment with antibiotics.

2. The lipid-soluble Prontosil after oral or intraperitoneal administration is partly excreted in the bile as a polar conjugate, apparently an N-glucuronide, and this drug appears to be converted into sulphanilamide partly by metabolism by the body tissues and partly by enterofloral metabolism.

3. The polar, water-soluble Neoprontosil is poorly absorbed from the intestine and when given orally is largely reduced to sulphanilamide by the gut flora before absorption. When given intraperitoneally, a large proportion (up to 70%) of the drug is excreted in the bile unchanged, and it would appear that only a small proportion of the drug (ca. 20%) is converted to sulphanilamide in the tissues, the major conversion occurring in the intestine after biliary excretion.

4. The reduction of Neoprontosil by the tissues is stimulated by pretreatment of the animals with phenobarbitone, but its reduction by the gut flora is unaffected by phenobarbitone pretreatment.

5. The conversion of Prontosil and Neoprontosil to sulphanilamide in the rat is an example of drug activation by the intestinal flora.     

The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmacodynamics of methadone

AIMS: There is considerable unexplained interindividual variability in the methadone dose-effect relationship. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of many drugs. Evidence suggests that methadone is a P-gp substrate in vitro, and P-gp affects methadone analgesia in animals. However the role of P-gp in human methadone disposition and pharmacodynamics is unknown. This investigation tested the hypothesis that the intestinal absorption and pharmacodynamics of oral and intravenous methadone are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe. METHODS: Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in healthy subjects. Pupil diameters and/or plasma concentrations of methadone and the primary metabolite EDDP were measured after 10 mg intravenous or oral methadone HCl, dosed 1 h after oral quinidine (600 mg) or placebo. RESULTS: Quinidine did not alter the effects of intravenous methadone. Miosis t(max) (0.3 +/- 0.3 vs 0.3 +/- 0.2 h (-0.17, 0.22)), peak (5.3 +/- 0.8 vs 5.1 +/- 1.0 mm (0.39, 0.84)) and AUC vs time (25.0 +/- 5.7 vs 26.8 +/- 7.1 mm h (-6.1, 2.5)) were unchanged (placebo vs quinidine (95% confidence interval on the difference)). Quinidine increased (P < 0.05) plasma methadone concentrations during the absorptive phase, decreased t(max) (2.4 +/- 0.7 vs 1.6 +/- 0.9 h (0.33, 1.2)), and increased peak miosis (3.2 +/- 1.5 vs 4.3 +/- 1.6 mm (-1.96, -0.19)) after oral methadone. The C(max) (55.6 +/- 10.3 vs 59.4 +/- 14.1 ng ml(-1) (-8.5, 0.65)) and AUC of methadone (298 +/- 46 vs 316 +/- 74 ng ml(-1) h (-54, 18)) were unchanged, as were the EDDP : methadone AUC ratios. Quinidine had no effect on the rate constant for transfer of methadone between plasma and effect compartment (k(e0)) (2.6 +/- 2.6 vs 2.5 +/- 1.4 h(-1) (-3.5, 4.2)). CONCLUSIONS: Quinidine increased the plasma concentrations of oral methadone in the absorptive phase and the miosis caused by methadone, suggesting that intestinal P-gp affects oral methadone absorption and hence its clinical effects. Quinidine had no effect on methadone pharmacodynamics after intravenous administration, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp does not appear to be a determinant of the access of methadone to the brain.     

Quinidine as a probe for the role of p-glycoprotein in the intestinal absorption and clinical effects of fentanyl

The mechanism of individual variability in the fentanyl dose-effect relationship is unknown. The efflux pump P-glycoprotein (P-gp) regulates brain access and intestinal absorption of numerous drugs. Evidence exists that fentanyl is a P-gp substrate in vitro, and P-gp affects fentanyl analgesia in animals. However, the role of P-gp in human fentanyl disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous fentanyl are greater after inhibition of intestinal and brain P-gp, using the P-gp inhibitor quinidine as an in vivo probe. Two randomized, double-blind, placebo-controlled, balanced, two-period crossover studies were conducted in normal healthy volunteers (6 males and 6 females) after obtaining informed consent. Pupil diameters and/or plasma concentrations of fentanyl and norfentanyl were evaluated after oral or intravenous fentanyl (2.5 microg/kg), dosed 1 hour after oral quinidine (600 mg) or placebo. Quinidine did not alter the magnitude or time to maximum miosis, time-specific pupil diameter, or subjective self-assessments after intravenous fentanyl but did increase the area under the curve (AUC) of miosis versus time (13.6 +/- 5.3 vs. 8.7 +/- 5.0 mm*h, p< 0.05) and decreased the effect of elimination (k(el) 0.35 +/- 0.16 vs. 0.52 +/- 0.24 h(-1), p < 0.05). Quinidine increased oral fentanyl plasma C(max) (0.55 +/- 0.19 vs. 0.21 +/- 0.1 ng/mL) and AUC (1.9 +/- 0.5 vs. 0.7 +/- 0.3 ng*h*mL(-1)) (both p < 0.05) but had no effect on apparent elimination. Plasma norfentanyl/fentanyl AUC ratios were not diminished by quinidine. Quinidine significantly increased maximum miosis after oral fentanyl (3.4 +/- 1.3 vs. 2.3 +/- 1.3 mm, p< 0.05), commensurate with increases in plasma concentrations, but concentration-effect relationships and the rate constant for the transfer between plasma and effect compartment (k(e0)) (1.9 +/- 1.0 vs. 3.6 +/- 2.6 h(-1)) were not significantly different. Quinidine increased oral fentanyl plasma concentrations, suggesting that intestinal P-gp or some other quinidine-sensitive transporter affects the absorption, bioavailability, and hence clinical effects of oral fentanyl. Quinidine had less effect on fentanyl pharmacodynamics, suggesting that if quinidine is an effective inhibitor of brain P-gp, then P-gp appears to have less effect on brain access of fentanyl.     

Effects of quinidine on antinociception and pharmacokinetics of morphine in rats

Aim The aim of this study was to investigate the effect of quinidine, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats. Methods Rats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined. Key findings The antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1‐fold greater area under the effect–time curve than that in vehicle‐treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration–time curve after oral or intravenous administration of morphine was increased 5.2‐ and 1.7‐fold, respectively, in quinidine‐pretreated rats compared with vehicle‐pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain‐to‐plasma concentration ratio was not changed. Conclusions Oral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P‐glycoprotein by quinidine.