Absorption Of Antipyrine Research Articles

Measurement of Mammary Blood Flow in Lactating Camels (Camelus dromedarius) Using Antipyrine Absorption Method

Mammary blood flow has been measured in human breast as well as cow, sheep and goat udders. According to the available literature, mammary blood flow has not been measured in lactating camels. So, the objective of this research was to measure mammary blood flow (MBF) in lactating camel. Data from two lactating camels were used to measure MBF using the antipyrine absorption method. Following complete manual removal of the milk from the udder, 3g of antipyrine dissolved in 30mL of distilled water was injected into each udder gland by the teat orifice. Blood samples were collected simultaneously from the left and right milk veins and pulmonary artery at 15, 20, 25, 30, 35, and 40 minutes following the infusion of antipyrine. Oxytocin (20IU) was injected intravenously 45 min following the infusion of antipyrine, and the volume of the milk removed by manual milking from each udder quarter was measured. Concentrations of antipyrine in the milk and blood were calculated, and MBF per udder gram per minute was measured. Results showed MBF of 6250ml/min (9000L/24h) for camel number 1 and 7800ml/min (11232L/24h) for camel number 2. Blood to milk ratios were 1200:1 and 1021:1 for camel number 1 and 2, respectively. MBF per gram of udder weight was 735.29ml/min/g and 829.78ml/min/g for camel number 1 and 2, respectively.

Differences in the promotion mechanism of the colonic absorption of antipyrine, phenol red and cefmetazole.

The promotion of antipyrine, phenol red and cefmetazole absorption by sodium ethylenediaminetetraacetate (EDTA-Na) as a paracellular promoter, diethyl maleate (DEM) as a transcellular promoter, and sodium taurocholate (TC-Na), whose promotion mechanism is still unclear, has been investigated by the rat in-situ colonic loop technique. All these promoters increased AP absorption and water influx from the lumen to the blood. Ouabain treatment suppressed the increase in antipyrine absorption and water influx induced by TC-Na and EDTA-Na, but did not modify the enhancing effect of DEM. Thus, the promotion mechanism of TC-Na may be similar to that of EDTA-Na. Phenol red and cefmetazole absorption were increased by TC-Na and EDTA-Na but not by DEM. Accordingly, phenol red and cefmetazole absorption appears to be promoted via paracellular but not transcellular routes. The collection of blood for plasma samples reduced the influx of water which had been increased by TC-Na or EDTA-Na. Consequently, the enhancement in antipyrine plasma concentration by these promoters was reduced to the control level. The inhibitory mechanism for this is discussed on the basis of the blood-flow limitation of antipyrine and water absorption.

Tigecycline and cyclosporine interaction—an interesting case of biliary-excreted drug enhancing the oral bioavailability of cyclosporine

To the Editor: Stumpf et al. (2009) have reported an interesting observation of enhanced blood levels of cyclosporine in a renal transplant patient upon co-medication with tigecycline [1]. The interaction between the two agents was found to be acute in nature and necessitated a dose reduction of cyclosporine to avoid safety concerns. Upon the cessation of tigecycline treatment, the dosing of cyclosporine had to be restored to its original level to avoid graft rejection due to lower efficacy [1]. The observations made in this case study are important ones since there is a myth that drugs administered through two different routes are less likely to show a pharmacokinetic interaction. Additionally, it provides rational information in our understanding of the issues associated with an intravenously administered drug (tigecycline) versus an orally administered drug (cyclosporine). While the authors have proposed p-glycoprotein (pgp) effux transporters as possible culprits for this pharmacokinetic interaction [1], this communication attempts to bring in additional views for consideration to explain this intriguing phenomenon. Although Stumpf et al. do not report the route of administration of cyclosporine, it is presumed that the renal transplant patient was on a oral dose of cyclosporine [1]. As described by the authors [1], the oral bioavailability of cyclosporine is highly variable owing to the concomitant effects of cytochrome P450 (CYP) metabolism (CYP3A4/ 3A5) and pgp-related efflux transport activity [2]. Upon the addition of tigecyline treatment, there was an acute increase in the blood concentrations of cyclosporine suggesting an enhanced oral bioavailability of cyclosporine [1]. The altered bioavailability of cyclosporine could have been achieved by two different possibilities. Firstly, as described by Stumpf et al., since tigecycline is excreted in bile (almost 59% of the administered dose [3]), it is likely that tigecycline would have impaired pgp-mediated gut efflux of cyclosporine resulting in an increased oral bioavailability. Secondly, as an alternate possibility, since cyclosporine is also known to undergo biliary excretion, perhaps there was a preferential biliary excretion of tigecycline as opposed to cyclosporine (direct competition) and/or inhibition of the biliary excrection of cyclosporine by tigecycline leading to the increased blood concentrations of cyclosporine. However, paradoxically, cyclosporine has been shown to increase the plasma concentrations of mycophenolic glucuronide due to the direct inhibition of its biliary excretion pathway [4]. While the above speculative possibilities could account for the observed enhanced bioavailability of cyclosporine in the presence of tigecylcline, one has to closely evaluate the recently reported data from the interaction study of tigecycline and digoxin [5]. Interestingly, tigecycline failed to show an interaction with digoxin, a well known and widely used probe substrate for pgp-mediated efflux [5]. Therefore, a key question to ask should be why tigecylcine would preferentially affect the pgp efflux of cyclosporine but not digoxin. A recent work published by Igel et al. (2008) sheds some light on the specificity of the involvement of apically located pgp transporters for the absorption and transport of digoxin [6]. The use of a pgp inhibitor such as quinidine in the study effectively increased the absorption of digoxin [6]. However, the bioavailability and oral absorption of antipyrine, which undergoes paracellular absorption, was Eur J Clin Pharmacol (2009) 65:543–544 DOI 10.1007/s00228-009-0631-x

A porcine model for fixed drug eruptions in humans: the case of antipyrine in the Yucatan micropig

To date, there is no acceptable animal model to investigate fixed drug eruptions (FDEs) in humans. We briefly report here observations suggesting that the Yucatan micropig may be a useful animal model for that purpose. During an investigation of antipyrine absorption and disposition, we observed the development of FDEs after intravenous administration of a 1 g dose. Our observations were consistent with those reported in several investigations of humans taking a single dose of antipyrine. To confirm these results, a naïve micropig was challenged. A male uncastrated Yucatan micropig (27.2 kg) was given a 1 g dose of antipyrine intravenously. After 30 days, this pig was rechallenged with the same intravenous dose of antipyrine (1 g). Blood samples were obtained to examine immunological endpoints. During the initial challenge, a fluid plaque (ca. 1-1.5 cm) appeared on the left hip of the pig ca. 6 h after dosing. After the rechallenge, inflamed pink patches were observed at the same sites where the blisters formed initially; however, no blisters re-formed. Changes of neutrophil, lymphocyte and eosinophil levels from baseline were noted 8 h after challenge. The micropig did not seem otherwise affected by the FDEs. These observations suggest that the Yucatan micropig, or swine in general, may be a useful animal model for detecting drugs that may cause FDEs in humans.

Membrane permeability and antipyrine absorption in a rat model of ischemic colitis

The aim of this study was to determine whether the duration of ischemia affects antipyrine absorption in the large intestine. This was carried out in a rat model of ischemic colitis in which ischemia and associated inflammation was induced by marginal vessel ligation. Blood flow was disrupted by positioning an o-ring around the distal rectum and ligating the marginal vessel at two locations in the hind-gut ligament artery region. Ligation was performed for 1, 2, 3, and 5 h. We assessed large intestine damage by measuring key indicators of inflammation, myeloperoxidase (MPO) activity and thiobarbituric acid reactant substrates (TBARS) in the mucosa and by histological staining with hematoxylin–eosin stain. Antipyrine membrane permeability was assessed in Ussing-type diffusion chambers, and related pharmacokinetics were calculated from antipyrine plasma concentration measurements following colon administration of the drug. Vessel ligation caused some sloughing of epithelial cells and elevated the MPO and TBARS levels. Prolonged ligation failed to affect the apparent permeability coefficient ( P app) of antipyrine. Prolonged ligation, however, gradually increased plasma antipyrine concentrations to near control levels. This increase was paralleled by increases in the absorption rate constant AUC and antipyrine bioavailability. Taken together, these results suggest that the absorption kinetics of antipyrine may depend on blood flow changes in the large intestine that occur with inflammation.

19] Antipyrine, theophylline, and hexobarbital as in vivo P450 probe drugs

This chapter focuses on antipyrine (AP), hexobarbital (HB), and theophylline (TH) as probe drugs for in vivo characterization of specific P450 enzymes. AP is the commonly used substrate in estimating the influence of all kinds of endogenous and exogenous factors on P450 enzyme activities. AP, HB, and TH can be used in experimental animals and in humans without side effects at the dose levels required for determination of P450 enzyme activity. Absorption of AP, TH, and HB from an oral solution is rapid and complete. They have been used alone, but also in combination with each other or other probe drugs. The chapter describes the methods that are reliable in estimating the pharmacokinetics of AP, TH, and HB. These model substrates have been applied very extensively in studying the influence of environmental and disease conditions on P450 enzyme activities both in humans and in experimental animals. Thereby, much insight has been obtained in the factors governing overall oxidative drug-metabolizing enzyme activity in vivo . Studies with other probe drugs, which are more specific for single P450 enzymes, are needed to elucidate selectivity in altered enzyme activity.

The Lack of Effect of Induced Net Fluid Absorption on thein vivoPermeability of Terbutaline in the Human Jejunum

The absorption mechanism(s) of terbutaline in the human jejunum was studied by using the intestinal perfusion instrument, Loc-I-Gut. The present study was divided into three parts. In Part I the absorption of 10 and 20 microM of both (+) and (-)-terbutaline enantiomers was studied. The influence of D-glucose (80 mM) on the net fluid transport across the intestinal wall and the effective intestinal permeability (Peff) of both (+/-)-terbutaline (10 microM) and antipyrine (0.5 mM) was investigated in Part II. The experimental design of Part III was similar to that in Part II, with the exception that the perfusion solution was hypotonic and had a D-glucose concentration of 80 mM. No statistical differences were found in the Peff between terbutaline enantiomers or their concentrations. D-glucose (80 mM) did neither affect net fluid transport nor the Peff of (+/-)-terbutaline and antipyrine in the human jejunum. In contrast, hypotonic D-glucose (80 mM) solution induced a net fluid absorption (p < 0.01). In parallel with this observation, the Peff -value of (+/-)-terbutaline was unchanged, whereas the absorption of antipyrine was found to be significantly increased (p < 0.05). The increased permeability of antipyrine during the net fluid absorption phase might be due to convective paracellular flow, but more likely is it a consequence of a higher concentration gradient of the drug close to the intestinal wall, and thereby increased transcellular absorption. Based on these findings we propose that the major route for the oral absorption of terbutaline and antipyrine might be passive transcellular diffusion.

Effects of bladder resorption on pharmacokinetic data analysis

In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (ka), interval between bladder voiding (delta tvoid), ratio of renal elimination rate constant to overall elimination rate constant (ex:kel ratio), and kel or t1/2. The data identified ka, delta tvoid, and kex:kel ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values of ka, delta tvoid, and kex:kel ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CLrenal), total body clearance (CLtotal), nonrenal clearance (CLnonrenal), t1/2, mean residence time (MRT), amount and fraction of dose excreted in urine (Aex and fe), and volume of distribution at steady state (Vdss). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plasma concentration-time profile, MRT and t1/2, but decreased CLrenal, CLtotal, Aex, and Fe. Vdss was relatively unchanged. Overestimation of MRT and t1/2 was dependent on ka, kex:kel ratio, and delta tvoid. Underestimation in CLrenal), Aex, and fe was not dependent on the Kex:kel ratio, but was affected by changes in ka and delta tvoid. CLrenal and fe were the most sensitive pharmacokinetic parameters, with a > or = 50% underestimation at a ka value that we reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over- or underestimation in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption.

The effect of L-leucine on the absorption of levodopa, studied by regional jejunal perfusion in man.

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L-leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L-leucine decreased the intestinal absorption of levodopa from 40 +/- 19 to 21 +/- 15% but was without effect on the absorption of antipyrine, benserazide and D-glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.

The use of a perfluorochemical emulsion as a vascular perfusate in drug absorption.

In-vitro simultaneous luminal and vascular perfusion using the perfluorochemical emulsion, FC-43 emulsion, as a vascular perfusate, was examined for drug absorption in rat jejunum. The intestinal membrane in this system was found to retain its normal barrier functions for drug transport, as evident from the following: (i) stable absorption clearance of tritiated water and salicylic acid at steady-state, (ii) agreement of this clearance with that by in-situ single-pass luminal perfusion, (iii) active transport of D-glucose and its inhibition by phloridzin and (iv) normal glutamate pyruvate transaminase activity in the intestinal mucosa. FC-43 emulsion gave a more normal absorption site blood flow than the usual vascular perfusate containing erythrocytes and albumin in Krebs-Henseleit bicarbonate buffer solution. Consequently, this emulsion was useful for examining the contribution of blood flow resistance toward drug absorption. The rate-limiting steps of absorption of tritiated water, antipyrine and salicylic acid were examined by perfusion using FC-43 emulsion. The absorption of tritiated water was almost completely blood flow-limited and its absorption clearance may possibly be an approximated absorption site blood flow. The contribution of blood flow resistance to total resistance for antipyrine absorption exceeded that for salicylic acid absorption.

Antipyrine absorption and disposition in the elderly.

Twelve young (24-41 years) and 11 elderly (62-77 years) volunteer subjects received a single 1.0-gram dose of antipyrine on three occasions: intravenously, orally in the fasting state and orally following a standard breakfast. Plasma antipyrine concentrations were determined for 24 h after each dose. Compared to young males, elderly men had significantly prolonged elimination half-life (17 vs. 11 h, p less than 0.025) and reduced clearance (32 vs. 54 ml/min, p less than 0.06). However, elderly and young women did not differ in half-life (12 vs. 11 h) or clearance (37 vs. 44 ml/min). After oral dosage in the fasting state, young and elderly groups (regardless of gender) did not differ in peak plasma antipyrine concentration (Cmax) or time of peak concentration (Tmax). Absolute bioavailability was not significantly less than 100% and was not related to age. Postprandial oral dosage of antipyrine caused reduced Cmax and prolonged Tmax in all groups, but absolute bioavailability was not significantly less than 100%. Again, there were no age-related differences. Although aging may lead to reduced clearance of antipyrine among men, there is no evidence that old age is associated with impairment of the rate or extent of antipyrine absorption from the gastrointestinal tract.

Relationship between antipyrine absorption and blood flow rate in rat jejunum, ileum, and colon.

The appearance rate of antipyrine in intestinal venous blood was measured in anesthetized rats during perfusion (0.2 ml/min) of a buffered solution with 1 mmol/l labeled antipyrine through a jejunal, ileal, or colonic segment (length: 2-5 cm). When the blood flow rate was increased from 0.9-1.2 to 1.6-2.0 ml min-1 g-1 by raising the systemic blood pressure from 80 to 130 mm Hg, the absorption of antipyrine increased only in the colon. Stepwise reduction of the blood flow rate from 1.4-1.7 to 0.2-0.3 or stepwise raise from 0.2-0.3 to 1.4 ml min-1 g-1 by constriction or release of the mesenteric artery decreased or increased the absorption rate of antipyrine. The relation between absorption and flow rate can be described by curves which ascend at low and level off into a horizontal section at high flow rates. At the same blood flow rate the regional absorption rate decreased in the order jejunum, ileum, and colon with the largest step between ileum and colon. Model analysis yielded the following results for jejunum, ileum, and colon, respectively: permeability-surface area product 0.083, 0.074, and 0.037 ml min-1 g-1; fraction of absorptive site blood flow rate 0.24, 0.19, 0.08. The differences can be attributed mainly to the change of the surface area from jejunum to ileum and colon.

Influence of dietary fiber and intraluminal pressure on absorption and pre-epithelial diffusion resistance (unstirred layer) in rat jejunum in situ.

The appearance rates of antipyrine, benzoic acid, benzylamine, urea, and alpha-methyl-D-glucoside (MG) in jejunal venous blood of anesthetized rats were measured with and without dietary fibers methylcellulose, carboxymethylcellulose sodium, guaran, and sodium alginate in the luminal solution. Raising the concentration of methylcellulose from 0 to 17.5 g/l resulted in an exponential increase in the viscosity of the solution to 98 cSt, a linear decrease of the diffusion coefficient for antipyrine by 28%, and an increase in antipyrine absorption in the perfused jejunal segment by 23%. The simultaneous increase in intraluminal pressure and radius resulted in a linear relation between absorption rate and apparent mucosal surface area. Similar results were obtained by raising intraluminal pressure directly using a carbohydrate-free perfusion solution. In the perfused rat jejunum, the effect of increased pre-epithelial diffusion resistance (i.e. reduced diffusion coefficient and lengthened diffusion distance) induced by methylcellulose on absorption was overcome by the effect of the enlarged apparent mucosal surface area. Preperfusion of a substrate-free, guaran containing solution followed by perfusion with a guaran-free solution containing antipyrine and MG retarded the increase in the appearance rate of these substrates due to the additional viscous guaran layer left after preperfusion. Constant distension of the intestinal wall was achieved by injecting 0.5 ml of the solution into a closed jejunal segment. Addition of the carbohydrates to the injection solution (approx. 100 cSt viscosity) resulted in a 3% to 20% reduction in the diffusion coefficients and in the absorption of antipyrine, benzoic acid, and MG. Diffusion coefficients for urea and benzylamine were reduced by 5% to 12%; absorption varied in the range of the control (-22% to +43%). Model analysis revealed that, in the closed jejunal segment of the rat, the limiting step in the absorption process of antipyrine, benzoic acid, and MG was pre-epithelial diffusion resistance; the reduction of absorption, therefore, corresponded roughly to that of the diffusion coefficient. In the case of urea and benzylamine, pre-epithelial diffusion resistance was only 20% of the total permeation resistance: the influence of the polymers on absorption, therefore, was not always significant.

Promotion of drug rectal absorption related to water absorption.

Promotion of the rectal absorption of antipyrine by sodium caprate (CA-Na) and diethyl maleate (DEM) was examined by in situ recirculating perfusion in the rat and compared with the results obtained previously with sodium ethylenediaminetetraacetate (EDTA-Na), a paracellular promoter. Both CA-Na and DEM significantly increased antipyrine absorption clearance (CLAP)and water inflex, in the same way as EDTA-Na. The increased levels of both CLAP and water influx caused by CA-Na were reduced to the control levels by ouabain, as was also found in the case of EDTA-Na. However, the promoting effect of DEM was decreased only slightly (not significantly) by ouabain treatment. These results indicate that the promotion mechanisms of CA-Na and DEM are different and that CA-Na works as a paracellular promoter in a manner similar to EDTA-Na.Antipyrine absorption through the paracellular route may possibly be promoted by water absorption dependent on active sodium transport.

The promotion of drug rectal absorption by water absorption.

The promotion of the rectal absorption of antipyrine by sodium taurocholate (TC-Na) or sodium ethylenediaminetetraacetate (EDTA-Na) has been examined by in-situ recirculating perfusion in the rat. These promoters significantly increased water influx, efflux and antipyrine absorption clearance (CLAP). Ouabain treatment significantly reduced the increase in both rectal absorption of drug and water flux. Water absorption dependent on active sodium transport may thus possibly promote the rectal absorption of poorly absorbable drugs.

Promoting mechanism by bile salt related to water absorption in drug rectal absorption.

The promoting mechanism by bile salts in rat rectal absorption of antipyrine was studied by the in situ recirculating perfusion. The significant correlation between rectal absorption clearance (CLAP) of antipyrine (AP) and apparent water influx (influx') was found in the control without promoters, indicating the existence of solvent drag in the AP rectal absorption. Sieving coefficient of AP (bAP), i.e. the slope of the regression line between CLAP and influx', was 0.6 approximately equal to that in small intestine reported previously. The relation between the promoting effects and solvent drag was further studied, resulting that both CLAP and influx' were significantly enhanced by sodium taurocholate (TC-Na), sodium glycocholate (GC-Na) and sodium cholate (C-Na). Accordingly the promoting effects of bile salts might be due to the increase in solvent drag. However TC-Na did not produce the significant change in bAP. From these results, the enhancing mechanism in the epithelial cell membrane transport was discussed.

Antipyrine absorption after delayed oesophageal capsule transit.

Twenty fasted patients were given hard gelatin capsules containing antipyrine and barium, and in ten patients the capsule arrested and disintegrated in the oesophagus. Plasma antipyrine was assayed at 10 min intervals for 1 h, then 30 min intervals for a further 3 h. The plasma concentration-time curves for the patients in whom the capsule entered the stomach rapidly, and for those in whom the capsule lodged in the oesophagus, were compared. The absorption in the first hour was calculated from the area under the plasma concentration-time curve and found to be significantly lower if the capsule disintegrated in the oesophagus (P less than 0.0005). The time to peak plasma concentration was delayed by an average of 46 min (P less than 0.01) and the peak plasma concentration was significantly lower (P less than 0.05) if delayed capsule transit occurred. Delayed capsule transit through the oesophagus significantly changed the pharmacokinetic profile of antipyrine.

A non-invasive method for the study of hepatic drug metabolism in rodents: Antineoplastic drug effects on antipyrine metabolism in mice

A rapid, sensitive and simple high pressure liquid chromatography (HPLC) method is described for the direct analysis of antipyrine in saliva. The detection limit was found to be 1.0 ng/ml of sample, lower than any previously reported method. Accuracy and precision were maintained with as little as 0.5 μl of saliva. Thus the rate of elimination of antipyrine has been monitored non-invasively in rats and for the first time in mice. The antipyrine half-life was found to be 28.9 ± 4.0 (S.E.M.) min and 111 ± 20 min in mice and rats, respectively. In mice single i.p. doses of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) (30 mg/kg) produced increases in antipyrine half-life, up to 28 days post-treatment. The maximum effect of BCNU was observed on day 7 with an antipyrine half-life of 74.4 ± 15.7 min. Phenobarbital induction lowered the antipyrine half-life in controls to 12.6 ± 1.2 min. An enhanced inductive effect was observed in BCNU-treated mice: BCNU-treated, phenobarbital-induced mice displayed a half-life for antipyrine of 7.4 ± 0.6 min on day 21 post BCNU dose. These effects could not be attributed to changes in absorption of antipyrine in BCNU-treated mice.

The effect of antineoplastic drugs on the pharmacokinetics of antipyrine in the rat.

The pharmacokinetics of antipyrine was investigated in individual rats pretreated with cyclophosphamide, 5-fluorouracil and methotrexate. Before oral dosing a complete emptying of the rat stomach was obtained by 24 hours of fasting and prevention of coprophagy. Antipyrine was given intravenously via a cannula in an inguinal vein and repeated samples of blood were drawn from a cannula in an inguinal artery. Systemic availability of oral antipyrine was studied in rats given the 14C-labelled drug intravenously and the 3H-labelled drug orally after pretreatment with cyclophosphamide. The log plasma concentration versus time curve of antipyrine given orally showed a short absorption and distribution phase followed by a linear elimination phase. Peak antipyrine concentrations were reached 3-6 minutes after oral dosing in control rats. The rate of absorption of antipyrine was moderately decreased by methotrexate. All drugs increased the area under the curve (AUC) of antipyrine. The systemic availability of oral antipyrine after cyclophosphamide pretreatment (0.88) was not changed, but the metabolic clearance of the drug was reduced. The apparent elimination rate constant was decreased by methotrexate and the apparent volume of distribution was decreased by cyclophosphamide and 5-fluorouracil. The results indicate that antineoplastic agents may change drug kinetics in different ways in rats.

The relevance of blood flow for the absorption of drugs in the vascularly perfused, isolated intestine of the rat

1. The absorption of antipyrine, salicylic acid, and urea was measured in vascularly perfused segments of rat intestine. The results were compared with absorption in segments of intestine which were prepared in an identical manner, but not perfused with blood. 2. Compared to in situ results obtained earlier, the absorption of antipyrine and salicylic acid increased 3-fold; the absorption of urea, 2-fold. The absorption of the drugs in the unperfused segments was reduced 60%; however, the absorption of urea remained unchanged. Blood flow apparently limits drug absorption, but not urea absorption. 3. A certain amount of the drugs permeated into the serosal bath in the blood-perfused segments of intestine: approximately 20% of the antipyrine and urea, but only 2% of the salicylic acid. This accounts for the difference between the disappearance rate and the venous appearance rate. 4. Histological examination revealed no morphological alterations in the blood-perfused segments when compared with control specimens. The water and glucose absorption rates were within the range obtained in earlier in vivo investigations. 5. The glucose consumption of the tissue was increased in the non-vascularly perfused intestine; apparently the oxygen supply was insufficient. The histological alterations may be the result of insufficient oxygen supply or water storage within the tissue.