Percutaneous Absorption and Excretion of Alacholr in Rhesus Monkeys

Percutaneous Absorption and Excretion of Alachlor in RhesusMonkeys. KRONENBERG, J. M., FUHREMANN, T. W., AND JOHNSON, D.E., (1988) Fundam Appl Toxicol 10, 664–671. The percutaneousabsorption and excretion profile of alachlor were evaluatedin rhesus monkeys. A preliminary study demonstrated that anaverage of 86.7 and 9.7% of the administered dose was recoveredin the urine and feces, respectively, following intravenousadministration of radiolabeled alachlor to rhesus monkeys. Insubsequent studies, diluted and undiluted emulsifiable concentrate(EC) and microencapsulated (ME) formulations of radiolabeledalachlor were applied to a 40-cm² shaved abdominal area andallowed to remain on the skin for 12 hr. The radioactivity excretionprofiles in all animals were comparable. In all cases, approximately88% of the absorbed dose was eliminated via the urine, primarilywithin the first 48 hr. Comparison of the amount of radiolabelrecovered in the topical studies with that recovered followingintravenous administration indicated that an average of 8.5and 3.7% of the alachlor in the topically applied EC and MEformulations, respectively, was absorbed.     

Excretion Profiles of the Mycotoxin Deoxynivalenol, following Oral and Intravenous Administration to Sheep

Excretion Profiles of the Mycotoxin Deoxynivalenol, followingOral and Intravenous Administration to Sheep. PRELUSKY, D. B.,VEIRA, D. M., TRENHOLM, H. L., AND HARTIN, K. E. (1986). Fundam.Appl. Toxicol. 6, 356–363. The excretion profiles of deoxynivalenol(DON) and metabolites (DON glucuronide conjugate, 3,715-trihydroxytrichothec-9,12-diene-8-one(DOM-1), and DOM-1 glucuronide conjugate) were defined in malesheep following either intravenous (iv) or oral administrationof the toxin at levels of 0.5 and 5.0 mg DON/kg body wt, respectively.After iv dosing, urinary DON levels declined in a biphasic fashionwith an average elimination half-life (terminal phase) of 1.2hr. diminishing to baseline concentrations by 8 hr. Maximumurinary excretion rates for the two major metabolites identified(conjugated DON, conjugated DOM-1) occurred 0.5–1.5 hrafter dosing, exhibiting elimination half-lives of 2.2 and 3.1hr, respectively. Total recovery accounted for only about 66.5%of the dose: 63.0% in the urine (24.1% DON, 21.2% conjugatedDON, 0.5% DOM-1, 17.2% conjugated DOM-1) and 3.5% in bile (madeup almost completely of conjugated DOM-1). The peak biliaryexcretion rate for conjugated DOM-1 was found to occur within1 hr postdosing, which rapidly declined to baseline levels by5 hr. Following oral administration, urinary excretion ratesof the major metabolites (DON, conjugated DON, conjugated DOM-1)reached maximum 6–9 hr post-treatment, and declined exponentiallywith t values of 3.2, 4.0, and 5.0 hr, respectively. Urinaryand biliary recovery of administered DON averaged approximately7.1%: 7.0% in urine (2.1% DON, 3.6% conjugated DON, 0.06% DOM-1,1.2% conjugated DOM-1) and 0.11% in bile (predominately conjugatedDOM-1). Between 54 and 75% of the oral dose was recovered inthe feces. These findings indicate that DON and metabolitesdo not persist in the body following either a single oral orintravenous dose of DON and are rapidly excreted. However, followingiv administration, a portion of the dose (33.5%) remained unaccounted,presumably converted to unidentified metabolites. Based on theseresults it appears that metabolism is the major process of eliminationof DON in sheep.     

Metabolism of Xenobiotics during Percutaneous Penetration: Role of Absorption Rate and Cutaneous Enzyme Activity

Metabolism of Xenobiotics during Percutaneous Penetration: Roleof Absorption Rate and Cutaneous Enzyme Activity. STORM, J.E., COLLIER, S. W., STEWART, R. F., AND BRONAUGH, R. L. (1990).Fundam. Appl. Toxicol 15, 132–141. The role of absorptionrate and enzyme activity on cutaneous metabolism of topicallyapplied xenobiotics was assessed by determining the simultaneouspercutaneous penetration/metabolism of benzo[a]pyrene (B[a]P)and 7-eth-oxycoumarin (7-EC) in intact, metabolically viableskin of Sencar mice, hairless guinea pigs, and humans. In addition,specific activities of aryl hydrocarbon hydroxylase (AHH) andethoxycoumarin deethylase (ECDE) were determined in cutaneousmicrosomal fractions. Both compounds were readily absorbed butonly minimally metabolized. Sencar mouse and hairless guineapig skin absorbed 55–60% of the applied B[a]P dose andmetabolized only 6 and 3%, respectively, of that absorbed. Humanskin absorbed 31% of the applied dose and B[a]P metabolism wasnot detectable. All three species absorbed 60–80% of theapplied 7-EC dose. Sencar mouse and hairless guinea pig skinmetabolized 1.3 and 1.2% of the absorbed dose, respectively,and human skin metabolized only 0.05%. When 7-EC absorptionwas increased to the maximum possible rate, its metabolism bySencar mouse and hairless guinea pig skin was also sub stantiallyincreased. In human skin, a much smaller increase in 7-EC absorptionrate was possible and no increase in 7-EC metabolism occurred.Thus relatively slower absorption of 7-EC and B[a]P by humanskin may limit cutaneous metabolism of these penetrating compounds.Specific activities of AHH and ECDE were significantly lowerin human skin than in Sencar mouse and hairless guinea pig skin,suggesting that low enzyme activity contributes as well to alow rate of metabolism by human skin compared to other species.Thus absorption rate and cutaneous enzyme activity are interrelateddeterminants of the extent of cutaneous metabolism of B[a]Pand 7-EC occurring during their percutaneous penetration, andslow absorption and low enzyme activity limit cutaneous metabolismof B[a]P and 7-EC in human skin in particular.     

大鼠静注苯妥英钠的毒代动力学研究

目的：探讨苯妥英钠（DPH—Na）在大鼠血液的毒代动力学规律及组织分布。方法：大鼠静注中毒剂量DPH-Na后采集血液及组织样品,HPLC法测定其血浆及组织中药物浓度,分别用隔室模型拟合和米曼氏方程计算毒代动力学参数,并比较各组织中药物浓度。结果：DPH-Na静注中毒剂量后,在大鼠体内符合二室模型过程,主要毒代动力学参数：Cmax=（61．31±7．09）ug·ml^-1,t1／2a：（0．18±0．08）h,t1／2 B：（2．60±0．52）h,AUC=（147．22±29．16）（ug·ml^-1）·h,CL=（0．15±0．02）L·h^-1。按米曼氏方程解析所得主要毒代动力学参数：Vm=（10．42±5．33）ug·ml^-1·h^-1,Km=（66．65±13．71）ug·ml^-1,其余毒代动力学参数与二室模型拟合结果无明显差异（P〉0．05）。DPH-Na在各组织中的浓度顺序依次为：肺〉肾〉肝〉心〉脑。结论：DPH-Na在大鼠体内的毒代动力学与药物动力学规律有差异,其中毒后在体内消除减慢,血液及组织中可能大量蓄积。     

Bioavailability of Enrofloxacin after Oral Administration to Fed and Fasted Pigs

Abstract: The disposition of enrofloxacin was measured after intravenous and oral administration to pigs. Eight clinically healthy pigs weighing 25 to 40 kg received a dose of 5 mg/kg intravenously and 10 mg/kg orally in both a fasted and a fed condition in a three-way cross-over design. Enrofloxacin was present in plasma for up to 72 hr after both intravenous and oral administration to fasted as well as fed pigs. The steady state volume of distribution was determined to 3.9±0.5 1/kg body weight which indicates that enrofloxacin was widely distributed in the body. The bioavailability was determined to 83±13% in fed and to 101±32% in fasted pigs. Based on the bioavailability and the resulting plasma concentrations it is concluded that a therapeutically active concentration for the most common porcine microbial pathogens are maintained for at least 24 hr after oral administration of 10 mg/kg body weight to fasted as well as to fed pigs. Ciprofloxacin which is an active metabolite of enrofloxacin was observed in plasma samples from all treated pigs, but the concentration never exceeded 0.1 μg/ml. During the first 24 hr after the administration of enrofloxacin the concentration of the metabolite made up less than 10% of the corresponding concentration of the parent compound.     

Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis

The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration–time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed‐effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two‐compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000–2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1–2 and three times higher in HNC patients with oral mucositis grade 3–4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25‐mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit.     

Recent Advances in Carrier-mediated Hepatic Uptake and Biliary Excretion of Xenobiotics

Purpose. Besides renal excretion, hepatic metabolism and biliary excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated transport contributes to hepatic uptake and/ or biliary excretion. In particular, primary active transport mechanisms have been shown to be responsible for the biliary excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary active excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as Phase III (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation. Methods. The transporters, which have been called P-glycoprotein (MDR), multidrug resistance related protein (MRP) and GS-X pump and which are believed to be involved in the primary active pumping of xenobiotics from the cells, are now known as the ATP-binding cassette (ABC) transporters. In this review, we first describe the HMG-CoA reductase inhibitor, pravastatin, as a typical case of a carrier-mediated active transport system that contributes to the liver-specific distribution in the body. Results. Regarding biliary excretion, we have summarized recent results suggesting the possible contribution of the ABC transporters to the biliary excretion of xenobiotics. We also focus on the multiplicities in both hepatic uptake and biliary excretion mechanisms. Analyzing these multiplicities in transport is necessary not only from a biochemical point of view, but also for our understanding of the physiological adaptability of the living body in terms of the removal (detoxification) of xenobiotics. Conclusions. Clarification of these transport mechanism may provide important information for studying the pharmacokinetics of new therapeutic drugs and furthermore, leads to the development of the drug delivery systems.     

Xenobiotics Inhibit Hepatic Uptake and Biliary Excretion of Taurocholate in Rat Hepatocytes

Reports suggest that troglitazone, and to a lesser extent bosentan,may alter bile acid homeostasis by inhibiting the bile saltexport pump. The present studies examined the hypothesis thatthese xenobiotics may modulate multiple hepatic bile acid transportmechanisms. In suspended rat hepatocytes, troglitazone (10 µM)decreased the initial rate of taurocholate uptake 3-fold; theinitial uptake rate of estradiol-17ß-D-glucuronide,a substrate of the organic anion transporting polypeptides,also was decreased 4-fold. Bosentan (100 µM) decreasedthe initial uptake rate of taurocholate and estradiol-17ß-D-glucuronideby 12- and 7-fold, respectively. In sandwich-cultured rat hepatocytes,10-min accumulation of taurocholate in cells + bile canaliculi(408 ± 57 pmol/mg protein) was decreased significantlyby troglitazone (157 ± 17 pmol/mg protein, respectively)only in the presence of Na⁺, the driving force for the sodiumtaurocholate cotransporting polypeptide. A similar decreasewith 10-fold higher concentrations of bosentan was noted. Thebiliary excretion index of taurocholate (55 ± 8%) wasdecreased in the presence of 10 µM troglitazone (27 ±2%) and 100 µM bosentan (10 ± 6%). In conclusion,xenobiotics may alter hepatic bile acid transport by inhibitingboth hepatic uptake and biliary excretion.     

Absorption,Distribution, and Excretion of Ammonium Perfluorooctanoate (APFO) After Oral Administration to Various Species

Male and female mice, rats, hamsters, and rabbits were treated with a single oral dose of ¹⁴C-ammonium perfluorooctanoate (APFO), and the excretion and tissue distributions were followed for 120 h (168 h in the rabbit). Substantial sex and species differences in the excretion and disposition of ¹⁴C-radioactivity derived from ¹⁴C-labeled APFO were observed in this study. The female rat and the male hamster excreted more than 99% of the original ¹⁴C activity by 120 h after dosing; conversely, the male rat and the female hamster excreted only 39% and 60% of the original ¹⁴C activity, respectively, by 120 h postdosing. The male and female rabbits excreted the ¹⁴C activity as rapidly and completely as the female rat and the male hamster, whereas male and female mice excreted only 21% of the original ¹⁴C activity by 120 h postdosing. The rapid excretors (female rat, male hamster, and male and female rabbits) contained negligible amounts of ¹⁴C in organs and tissues at sacrifice. The slow excretors exhibited the highest ¹⁴C concentrations in the blood and liver followed by the kidneys, lungs, and skin.     

Trimedoxime and HI-6: Kinetic Comparison after Intravenous Administration to Mice

Abstract: The intravenous pharmacokinetics of the oximes HI-6 (pyridinium-1-(((4-carbamoi 1-pyridinio)metoxy)rnethyl)-2-(hydroxyiminomethyl)dichloride monohydrate), (132.54 μmol/kg) and trimedoxime (1,1′-(1,3′-propanedyl)bis((4-hydroxyimino) methyl)-pyridinium dibromide), (55,98 μmol/kg) in mice was investigated. The concentrations of oximes in plasma determined by high pressure liquid chromatography (HPLC) corresponded to a two-compartment pharmacokinetic open model. The oximes were rapidly eliminated from mice plasma, with half-times of 57.93 min. for HI-6 and 108.08 min. for trimedoxime. Although the oximes passed from circulation into the tissues at approximately the same rate, their transport back to the central compartment was two-times slower in the case of trimedoxime: t_1/2k21 was 77.9 min. for trimedoxime and 41.7 min. for HI-6. The total body clearance (CI_tot) of HI-6 was about 25% higher than that of trimedoxime. The central compartment volume of HI-6 distribution (V₁) was greater, whereas the volume of distribution of the peripheral compartment (V₂) was lower for about 35% with respect to the corresponding parameters of trimedoxime. The calculated pharmacokinetic parameters for the oxime HI-6 and trimedoxime show that trimedoxime is eliminated more slowly in mice, and penetrates better into the peripheral comparment where it remains longer.     

Biodistribution and Excretion of Radiolabeled 40 kDa Polyethylene Glycol Following Intravenous Administration in Mice

The pharmacokinetics, excretion, and tissue distribution of [¹⁴C]-labeled polyethylene glycol–alanine (PEG–Ala) were determined after slow bolus administration into the femoral vein of male CD-1 mice. The pharmacokinetics of PEG–Ala in blood and plasma revealed a biphasic elimination with a terminal half-life of 20 h. Eighty-five percent of the excreted material was voided in the urine and the remaining amount was detected in the feces. PEG–Ala-derived radioactivity was widely distributed with detectable levels of radioactivity observed in all tissues examined. The highest concentration was observed in the kidneys followed by lungs, heart, and liver. Six hours after administration, PEG–Ala levels were significantly reduced in all tissues. Despite a slow prolonged decrease, radioactivity was still detectable after 28 days. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2362–2370, 2013     

Administration of L-3,4-dihydroxyphenylalanine to rats after complete hepatectomy-II. Excretion of metabolites

The excretion of metabolites of l-[3-¹⁴C]dihydroxyphenylalanine (l-[3-¹⁴C]DOPA) was studied after its injection into rats with complete hepatectomies and into control rats. Approximately 60 per cent of the dose (11 mg/kg; 20 μCi) of injected [¹⁴C]DOPA was excreted in urine in 24 hr by the control rats, and 11 per cent in bile. Although a similar percentage of the dose (69.4 per cent) was excreted by the hepatectomized rats into urine, excretion was at a slower rate. Decarboxylation of injected [¹⁴C]DOPA within 24 hr appeared to be as great in the hepatectomized rats as in the controls, but metabolism of 3,4-dihydroxyphenylethylamine (dopamine, DA) to norepinephrine was less. In the operated animals most of the DA was metabolized to 3,4-dihydroxyphenylacetic acid or to homovanillic acid. Little radioactivity was present in tissues at 24 hr after injection of l-DOPA into control rats or into hepatectomized rats; however, some radioactivity appeared to be bound to protein in some tissues in both groups of rats.     

Fentanyl Pharmacokinetics in Pregnant Sheep after Intravenous and Transdermal Administration to the Ewe

Fentanyl is used for pain treatment during pregnancy in human beings and animals. However, fentanyl pharmacokinetics during pregnancy has not been fully established. The aim of this study was to characterize fentanyl pharmacokinetics in pregnant sheep after intravenous and transdermal dosing during surgical procedure performed to ewe and foetus. Pharmacokinetic parameters reported for non‐pregnant sheep and nominal transdermal dose rate were utilized for a priori calculation to achieve analgesic fentanyl concentration (0.5–2 ng/ml) in maternal plasma. A total of 20 Aland landrace ewes at 118–127 gestational days were used. In the first protocol, 1 week before surgery, 10 animals received 2 μg/kg fentanyl intravenous bolus, and on the operation day, transdermal fentanyl patches at nominal dose rate of 2 μg/kg/hr were applied to antebrachium, and ewes were then given a 2 μg/kg intravenous bolus followed by an intra‐operative 2.5 μg/kg/hr infusion. In the second protocol, 10 animals received fentanyl only as transdermal patches on the operation day and oxycodone for rescue analgesia. The data were analysed with population pharmacokinetic modelling. Intra‐ and post‐operative fentanyl concentrations were similar and slightly lower than the a priori predictions, and elimination and distribution clearances appeared slower during than before or after the surgery. Transdermal patches provided sustained fentanyl absorption for up to 5 days, but the absorption rate was slower than the nominal dose rate and showed a high interindividual variability. Further research is warranted to evaluate the clinical relevance of the observations made in sheep.     

Adequacy of Rifampin Absorption after Jejunostomy Tube Administration

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high‐pressure liquid chromatography demonstrated a peak serum rifampin level (C_max) of 18 μg/ml and total rifampin exposure (area under the curve from 0–6 hours [AUC_0–6]) of 50.1 μg/ml. These are high compared with rifampin C_max and AUC_0–6 values reported in patients after oral rifampin administration; C_max tends to range between 4.0–10.5 μg/ml and AUC_0–6 7.0–52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C_max and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.     

Foetal Fentanyl Exposure and Ion Trapping after Intravenous and Transdermal Administration to the Ewe

Opioids given to pregnant and parturient women are relatively freely transferred across the placenta. Spinal, epidural and intravenous fentanyl has been studied in pregnant women and neonates, but foetal safety of fentanyl dosing with transdermal patch during pregnancy and labour is not sufficiently studied. Foetal pH is physiologically lower than maternal pH, and thus, opioids, which are weak bases, are ionized and may cumulate to foetus. Foetal asphyxia may further worsen acidosis, and ion trapping induced by low pH is assumed to increase the foetal exposure to opioids. Here, we show that no correlation between foetal acidosis and ion trapping of fentanyl could be found. In three experiments, 29 pregnant sheep were administered fentanyl with 2 μg/kg/h patch supplemented with IV boluses/infusion. Foetal exposure to fentanyl was extensive, median 0.34 ng/ml (quartiles 0.21, 0.42), yet drug accumulation to foetus was not observed, and median of foetal/maternal concentration (F/M) ratio was 0.63 (0.43, 0.75) during the first hours after the fentanyl administration. Low foetal pH and pH difference between ewe and the foetus did not correlate with fentanyl concentration in the foetus or F/M ratio. At steady‐state during the second patch worn, foetal plasma fentanyl was low, 0.13 ng/ml, and the median of F/M ratio was 0.69. Our results demonstrate that drug accumulation to foetus caused by ion trapping seen with some weak base opioids may not be that significant with fentanyl. These results have a clinical relevance when fentanyl is dosed to pregnant woman and the foetus is acidemic.     

Excretion and Metabolism of 1-Nitropyrene in Rats after Oral or Intraperitoneal Administration

Excretion and Metabolism of 1-Nitropyrene in Rats after Oralor Intraperitoneal Administration. DUTCHER, J. S., SUN, J. D.,BECHTOLD, W. E., and UKEFER, C. J. (1985). Fundam. Appl. Toxicol.5, 287–296. Many nitro-substituted polycyclic aromatichydrocarbons (NPAHs) have been identified as environmental pollutantsand have been found to be mutagens and carcinogens in bacteriaand mammalian systems. They require metabolism to express theirbiological activity. The metabolism and excretion of 1-nitropyrene(NP), a prevalent NPAH, by Fischer-344 rats after intraperitoneal(ip) or oral administration was studied. Radiolabeled NP wasadministered to rats (10 mg NP/kg body wt), and urine and feceswere collected for 7 days. After ip administration of [¹⁴C]NP,60% of the radioactivity was found in the urine and 20% in thefeces. Likewise, 55 and 35% of the orally administered ¹⁴C wasfound in urine and feces, respectively. Both urine and feceswere analyzed by high-pressure liquid chromatography for metabolites.The majority of the radioactivity in both urine and feces wasassociated with very polar metabolites, none accounting formore than 10% of the dose. Small amounts (less than 1% of thedose) of aminopyrene (AP), acetylaminopyrene, and NP were detected.A urinary metabolite (3–8% of the dose) was found thatconverted to acetylaminopyrene phenol (two isomers) when urinewas heated overnight at 37°C at pH 4.5. More of this metabolite(2.2 times) as well as AP (1.8 times), was excreted after oralthan after ip administration of NP. The NP metabolites foundin this study demonstrate that reduction of the nitro groupis a significant route of NP metabolism in rats. Since nitroreductionappears to be necessary in the activation of NPAHs to bacterialmutagens, this indicates that similar metabolic pathways arepresent in rats (catalyzed by mammalian and/or gut bacterialenzymes) and that activation of NPAHs to carcinogens or toxinsby nitroreduction is possible.     

Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg^?1) to control and alloxan-induced diabetes mellitus rats (AIDRs). After intravenous administration of azosemide to the AIDRs, the area under the plasma concentration-time curve (AUC) increased considerably (3120 compared with 2520 μg min mL^?1; P < 0.135) and the total body clearance decreased considerably (3.20 compared with 3.96 mL min^?1 kg^?1; P < 0.0593). The considerable reduction in time-averaged total body clearance in the AIDRs was a result of the significant decrease in renal clearance (1.01 compared with 1.55 mL min^?1 kg^?1) in the AIDRs, the non-renal clearance being comparable between the two groups of rats. After intravenous administration, the 8-h urinary excretion of azosemide (29.5 compared with 40% of intravenous dose; P < 0.0883) and one of its metabolites, M1 (2.15 compared with 2.60% of intravenous dose, expressed in terms of azosemide; P < 0.05) decreased in the AIDRs because of the impaired kidney function. The diuretic, natriuretic, kaliuretic and chloruretic efficiencies increased significantly in the AIDRs. After oral administration of azosemide, AUC decreased significantly in the AIDRs (115 compared with 215 μg min mL^?1) possibly because of the reduced gastrointestinal absorption of azosemide in the AIDRs. After oral administration of azosemide, the 8-h urine output decreased significantly in the AIDRs (9.32 compared with 16.1 mL per 100 g body weight) because of the significantly reduced 8-h urinary excretion of azosemide (3.00 compared with 9.14% of oral dose). After both intravenous and oral administration some pharmacokinetic and pharmacodynamic parameters of azosemide were significantly different in AIDRs.     

Differences in Response to Topical Irritants in Haired and Hairless Guinea Pigs

The hairless guinea pig offers the possibility of performing irritant studies without the use of depilatory agents or clipping. Studies have shown a response to allergens and simple irritants comparable to that of the haired guinea pig but with differences depending on substance and concentration used. Histoanatomical studies have demonstrated differences in cutaneous structure in the two strains, differences that might influence the response to complex low‐grade irritants such as composite vehicles. The purpose of this study was to compare the usability of hairless (HLGP) and clipped haired guinea pigs (CGP) in tolerability studies of composite formulations. The tolerability of six selected skin care formulations (SCF), known to cause a differentiated irritative response in the HLGP, was studied in 15 male CGPs and 15 male HLGPs. All animals were treated on a 5 × 5 cm area on each side of the dorsal trunk twice daily for 4 consecutive days with SCF. The tolerance of the different SCF was assessed by clinical assessment, measurement of transepidermal water loss (TEWL), and colorimetry (a*‐parameter). The results obtained using clinical scoring and noninvasive measurements were consistent for the HLGP. Colorimetry was found to be unsuited for the evaluation of cutaneous irritation in the CGP over a period of days as regrowth of fur will obfuscate the underlying erythema. Both species were able to differentiate between SCFs in relation to skin tolerance, and although the response pattern was somewhat different in the two species, the ranking of the SCF was essentially the same. However, HLGP appears to be a more suitable model for tolerability testing of composite formulations due to the avoidance of clipping, being both time‐consuming and having the risk of affecting the clinical outcome.     

Pharmacokinetic Studies of 5-Fluorouracil after Oral and Intravenous Administration in Man

Abstract The pharmacokinetic conditions for oral administration of 5-fluorouracil (5-FU) were investigated in 16 patients with malignant liver tumours. The concentration of 5-FU in portal and systemic blood was determined by a microbiologic method every 10 min. during 2 hours after oral or intravenous administration of a standard dose of 250 mg 5-FU (～ 4 mg/kg b.wt.) or 15 mg 5-FU/kg b.wt. The drug was rapidly absorbed after oral administration with peak values within 10–30 min. 25% of the lower and 40% of the higher oral dose reached the systemic circulation. The reduction of systemic bio-availability was partly accomplished by a loss in the gastrointestinal tract and partly by extraction by the liver. The hepatic extraction ratio was calculated to 0.56 and 0.26 after the lower and the higher dose respectively indicating a saturable process. The availability of 5-FU was significantly higher in portal blood than in systemic blood after oral administration. The opposite conditions were found after intravenous administration. Thus, oral administration of 5-FU to patients with malignant liver tumours seems rational.