Mammary Excretion Research Articles

Effects of Turmeric Powder on Aflatoxin M1 and Aflatoxicol Excretion in Milk from Dairy Cows Exposed to Aflatoxin B1 at the EU Maximum Tolerable Levels.

Due to the climatic change, an increase in aflatoxin B1 (AFB1) maize contamination has been reported in Europe. As an alternative to mineral binders, natural phytogenic compounds are increasingly used to counteract the negative effects of AFB1 in farm animals. In cows, even low dietary AFB1 concentrations may result in the milk excretion of the genotoxic carcinogen metabolite aflatoxin M1 (AFM1). In this study, we tested the ability of dietary turmeric powder (TP), an extract from Curcuma longa (CL) rich in curcumin and curcuminoids, in reducing AFM1 mammary excretion in Holstein–Friesian cows. Both active principles are reported to inhibit AFM1 hepatic synthesis and interact with drug transporters involved in AFB1 absorption and excretion. A crossover design was applied to two groups of cows (n = 4 each) with a 4-day washout. Animals received a diet contaminated with low AFB1 levels (5 ± 1 µg/kg) for 10 days ± TP supplementation (20 g/head/day). TP treatment had no impact on milk yield, milk composition or somatic cell count. Despite a tendency toward a lower average AFM1 milk content in the last four days of the treatment (below EU limits), no statistically significant differences with the AFB1 group occurred. Since the bioavailability of TP active principles may be a major issue, further investigations with different CL preparations are warranted.

Effects of curcuminoids on the toxicity and mammary excretion of Aflatoxins and their metabolites in dairy cows

Effects of curcuminoids on the toxicity and mammary excretion of Aflatoxins and their metabolites in dairy cows

Interaction of mammary bovine ABCG2 with AFB1 and its metabolites and regulation by PCB 126 in a MDCKII in vitro model.

The ATP-binding cassette efflux transporter ABCG2 plays a key role in the mammary excretion of drugs and toxins in humans and animals. Aflatoxins (AF) are worldwide contaminants of food and feed commodities, while PCB 126 is a dioxin-like PCB which may contaminate milk and dairy products. Both compounds are known human carcinogens. The interactions between AF and bovine ABCG2 (bABCG2) as well as the effects of PCB 126 on its efflux activity have been investigated by means of the Hoechst H33342 transport assay in MDCKII cells stably expressing mammary bABCG2. Both AFB1 and its main milk metabolite AFM1 showed interaction with bABCG2 even at concentrations approaching the legal limits in feed and food commodities. Moreover, PCB 126 significantly enhanced bABCG2 functional activity. Specific inhibitors of either AhR (CH233191) or ABCG2 (Ko143) were able to reverse the PCB 126-induced increase in bABCG2 transport activity, showing the specific upregulation of the efflux protein by the AhR pathway. The incubation of PCB 126-pretreated cells with AFM1 was able to substantially reverse such effect, with still unknown mechanism(s). Overall, results from this study point to AFB1 and AFM1 as likely bABCG2 substrates. The PCB 126-dependent increased activity of the transporter could enhance the ABCG2-mediated excretion into dairy milk of chemicals (i.e., drugs and toxins) potentially harmful to neonates and consumers.

Placental transfer and mammary excretion of a novel angiotensin receptor blocker fimasartan in rats.

BackgroundFimasartan (FMS) is a potent angiotensin receptor blocker for the treatment of mild to moderate hypertension. This study aimed to evaluate the transfer of FMS to fetus and breast milk in rats.MethodsIn order to study the transfer to the fetus and nursing pup, pregnant and nursing maternal rats were administered with FMS by a constant intravenous infusion to reach target plasma concentrations of 200 ng/mL and 100 ng/mL. The concentrations of FMS in plasma, placenta, amniotic fluid, fetus, and milk were determined by a validated LC-MS/MS assay.ResultsUpon constant intravenous infusion, the plasma FMS concentration reached the target steady state concentrations (Css = 200 ng/mL and 100 ng/mL) in 24 h. The tissue-to-plasma partition coefficients (Kp) for placenta, amniotic fluid, and milk were obtained based on the observed FMS concentrations in the tissues and Css. The Kp values for all tissues were not different between high (Css = 200 ng/mL) and low (Css = 100 ng/mL) dose groups. While the mean Kp of the placenta was 44.6–59.0 %, the mean Kp was 1.3–1.7 % for the amniotic fluid and 14.9–17.0 % for fetus. The mean Kp of milk was 10.4–15.2 %.ConclusionsPlacental transfer and milk excretion of FMS was relatively lower compared to other angiotensin receptor blockers.

Plasma kinetics, excretion in milk of eprinomectin, and its efficacy against Hypoderma spp. following topical administration in yaks.

The plasma pharmacokinetics and mammary excretion of eprinomectin weredetermined in dairy yaks following topical administration at a dose of 0.5mg/kg. The kinetics of plasma and milk concentrations were analyzed using a noncompartmental model. Plasma and milk concentrations of eprinomectin increased to reach maximal concentrations of 5.45±2.84 and 2.29±0.90ng/mL at a Tmax of 1.79±0.57 and 2.00±0.82days, respectively. The concentration of eprinomectin in plasma was remained >0.5ng/mL for more than 30days after administration. The mean residence times of eprinomectin in plasma and milk were 14.73±6.22 and 9.37±2.81days, respectively. The AUC value in plasma (55.89±18.16ng day/mL) was threefold greater than that in milk (18.02±6.48ng day/mL). The AUC milk/plasma ratio was 0.33±0.08. The systemic availability of eprinomectin in yaks was lower than that observed value in other domestic bovines. The low level of eprinomectin excretion in milk suggests that eprinomectin can be used in yaks with zero milk-withdrawal time. The efficacy of eprinomectin against naturally acquired larvae of Hypoderma spp. was also determined in yaks. Topically administrated eprinomectin at a dose of 0.5mg/kg was 100% efficacious against larvae of Hypoderma bovis, H.lineatum, and H.sinense.

Mammary excretion of cannabidiol in rabbits after intravenous administration.

The present study examined the distribution of cannabidiol into milk after an intravenous bolus injection (3 mg kg-1) to lactating rabbits. Drug concentrations in milk and serum were measured by HPLC. Cannabidiol was excreted into milk rapidly and the drug levels in milk increased over a 4-24-h period following the maternal injection. The mean milk to serum concentration ratio was 25.9, indicating a significant accumulation of the drug in milk.

Trimethoprim in sheep influence of pH and protein binding on mammary and renal excretion.

Summary In 8 experiments on 5 healthy ewes, trimethoprim was infused intravenously to maintain a constant plasma level throughout the experimental period. Trimethoprim was bound to the plasma and milk proteins in average amounts of 43 and 8.5 %, respectively. Trimethoprim was excreted into milk in concentrations higher than in blood plasma. Glomerular filtration, active tubular secretion and back diffusion are involved in the renal handling of this drug. Both the mammary and renal excretion of trimethoprim are markedly influenced by the pH of milk and urine; they are increased at lower pH values. Zusammenfassung Einflus des pH-Wertes und der Proteinbindung auf die Ausscheidung von Trimethoprim durch die Milchdruse und die Niere beim Schaf Bei 5 gesunden Schafen wurde in 8 Experimenten Trimethoprim intravenos infundiert und zwar so, das wahrend der ganzen Versuchszeit der Plasmaspiegel konstant blieb. An den Plasma- bzw. Milchproteinen wurde das Trimethoprim durchschnittlich zu 43 bzw. 8,5 % gebunden. In der Milch war das Trimethoprim in einer hoheren Konzentration vorhanden als im Blutplasma. In der Niere erfolgte eine glomerulare Filtration sowie eine aktive tubulare Sekretion und Ruckdiffusion des Wirkstoffes. Sowohl die Ausscheidung durch die Milchdruse als auch durch die Niere wurde durch den pH-Wert der Milch und des Urins wesentlich beeinflust, und zwar wurde sie durch eine pH-Senkung erhoht. Resume Influence de la valeur du pH et de la liaison proteinique sur la secretion du trimethoprim par la glande mammaire et les reins chez le mouton Du trimethoprim a ete infuse intraveineusement chez 5 moutons sains dans 8 experimentations de telle maniere que le taux du plasma resta constant durant tout l'essai. Le trimethoprim fut lie en moyenne pour 43 % aux proteines du plasma et pour 8,5 % aux proteines du lait. Le trimethoprim fut plus concentre dans le lait que dans le plasma sanguin. On a constate dans les reins une filtration glomerulaire, une secretion tubulaire active et une rediffusion du metabolite. La secretion par la glande mammaire et par les reins fut nettement influencee par le pH du lait et de l'urine; elle fut diminuee par un abaissement du pH. Resumen Influjo del pH y la fijacion proteica sobre la excrecion mamaria y renal de trimetoprima En 5 ovejas sanas se infundio en 8 experimentos trimetoprima por via intravenosa de forma tal que durante todo el tiempo que duro la experiencia permanecio constante el nivel plasmatico. La trimetoprima estaba ligada a las proteinas plasmaticas resp. lacteas en un 43 y 8,5 % como promedio. En la leche se hallaba la trimetoprima en una concentracion superior a la del plasma sanguineo. En el rinon se producia una filtracion glomerular, una secrecion tubular activa y la redifusion del principio activo. Tanto la excrecion mamaria como la renal de trimetoprima se encuentran bajo el influjo esencial del pH de la leche y de la orina; aumenta con valores bajos de pH.

Plasma and milk kinetic of eprinomectin and moxidectin in lactating water buffaloes ( Bubalus bubalis)

The pharmacokinetics and mammary excretion of moxidectin and eprinomectin were determined in water buffaloes ( Bubalus bubalis) following topical administration of 0.5 mg kg −1. Following administration of moxidectin, plasma and milk concentrations of moxidectin increased to reach maximal concentrations ( C max) of 5.46 ± 3.50 and 23.76 ± 16.63 ng ml −1 at T max of 1.20 ± 0.33 and 1.87 ± 0.77 days in plasma and milk, respectively. The mean residence time (MRT) were similar for plasma and milk (5.27 ± 0.45 and 5.87 ± 0.80 days, respectively). The AUC value was 5-fold higher in milk (109.68 ± 65.01 ng day ml −1) than in plasma (23.66 ± 12.26 ng day ml −1). The ratio of AUC milk/plasma for moxidectin was 5.04 ± 2.13. The moxidectin systemic availability (expressed as plasma AUC values) obtained in buffaloes was in the same range than those reported in cattle. The faster absorption and elimination processes of moxidectin were probably due to a lower storage in fat associated with the fact that animals were in lactation. Nevertheless, due to its high excretion in milk and its high detected maximum concentration in milk which is equivalent or higher to the Maximal Residue Level value (MRL) (40 ng ml −1), its use should be prohibited in lactating buffaloes. Concerning eprinomectin, the C max were of 2.74 ± 0.89 and 3.40 ± 1.68 ng ml −1 at T max of 1.44 ± 0.20 and 1.33 ± 0.0.41 days in plasma and milk, respectively. The MRT and the AUC were similar for plasma (3.17 ± 0.41 days and 11.43 ± 4.01 ng day ml −1) and milk (2.70 ± 0.44 days and 8.49 ± 3.33 ng day ml −1). The ratio of AUC milk/plasma for eprinomectin was 0.76 ± 0.16. The AUC value is 20 times lower than that reported in dairy cattle. The very low extent of mammary excretion and the milk levels reported lower than the MRL (20 ng ml −1) supports the permitted use of eprinomectin in lactating water buffaloes.

授乳婦の薬物療法時における乳児への影響

A survey of the literature was conducted to evaluate the influence of mothers’medications on breast-fed infants with regard to the excretion of drugs into breast milk,the adverse reactions produced in breast-fed infants and the factors influencing them.The reported adverse reactions were most frequently caused by central nervous system drugs,accounting for 52% of the total.They included sedation and lethargy.On examining the times after birth that reactions occurred and the estimated maximum doses received by infants in breast milk,we found that adverse reactions frequently occurred in the infants of less than 3 months old and were particularly frequent in those less than 7 days old.Also,the estimated maximum doses in breast-fed infants having adverse reactions were significantly higher than those in infants with no adverse reactions.For half of the drugs reported to cause adverse reactions,the estimated maximum doses were less than 5% of the maternal weight adjusted doses.An evaluation of total scores for maximum drug intake through breast-feeding,existence of adverse reactions in the literature,and infant development showed that 82% of drugs reported to cause adverse reactions had scores of 10 or above while 75% of drugs for which adverse reactions were not reported had scores of less than 10.Our findings suggested that a comprehensive evaluation of such factors as mammary excretion and infant growth status could play a significant role in the prediction of adverse reactions in breast-fed infants.

Pharmacokinetics and Mammary Residual Depletion of Erythromycin in Healthy Lactating Ewes

The aim of this investigation was to examine the pharmacokinetics and mammary excretion of erythromycin administered to lactating ewes (n = 6) by the intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes at a dosage of 10 mg/kg. Blood and milk samples were collected at pre-determined times, and a microbiological assay method was used to measure erythromycin concentrations in serum and milk. The concentration-time data were analysed by compartmental and non-compartmental kinetic methods. The serum concentration-time data of erythromycin were fit to a two-compartment model after i.v. administration and a one-compartment model with first-order absorption after i.m. and s.c. administration. The elimination half-life (t(1/2beta)) was 4.502 +/- 1.487 h after i.v. administration, 4.874 +/- 0.296 h after i.m. administration and 6.536 +/- 0.151 h after s.c. administration. The clearance value (Cl tot) after i.v. dosing was 1.292 +/- 0.121 l/h/kg. After i.m. and s.c. administration, observed peak erthyromycin concentrations (Cmax) of 0.918 +/- 0.092 microg/ml and 0.787 +/- 0.010 microg/ml were achieved at 0.75 and 1.0 h (Tmax) respectively. The bioavailability obtained after i.m. and s.c. administration was 91.178 +/- 10.232% and 104.573 +/- 9.028% respectively. Erythromycin penetration from blood to milk was quick for all the routes of administration, and the high AUC milk/AUC serum (1.186, 1.057 and 1.108) and Cmax-milk/Cmax-serum ratios reached following i.v., i.m. and s.c. administration, respectively, indicated an extensive penetration of erythromycin into the milk.

Pharmacokinetics and Mammary Elimination of Imidocarb in Sheep and Goats

The pharmacokinetics and mammary excretion of imidocarb dipropionate, a therapeutic/prophylactic agent against a variety of tick-borne hemoparasitic diseases in domestic animals, have been investigated in sheep and goats. A commercial formulation of imidocarb di-propionate was injected i.m. at a single dose of 3mg/kg of body weight in 7 mature lactating ewes and 8 lactating does in good health. Blood samples were collected for 48h after administration and milk samples were collected every 12h for 10 d. A weak cation-exchange solid-phase procedure was used to remove imidocarb from plasma. A hexane/isoamyl alcohol liquid-liquid procedure was adopted to extract the drug from the milk of sheep. The same method was used for goat milk after exposing the matrices to enzymatic digestion. The extracted samples were analyzed by HPLC. The i.m. disposition kinetics of imidocarb in the 2 species showed significant differences in the rate of elimination (0.0075±0.002 and 0.025±0.004 L/h in sheep and goats, respectively), being faster in ewes than in does. Nevertheless, a smaller area under the concentration-time curve (12.21±0.76 and 9.49±0.54μg/mL per h in sheep and goats, respectively), a larger volume of distribution (4.18±0.44 and 7.68±0.57 L/kg in sheep and goats, respectively), and a longer mean residence time (9.07±0.77 and 14.75±2.20h in sheep and goats, respectively) were found in goats, suggesting a more rapid and effective drug storage in tissues during the first 48h after the injection. The concentrations of imidocarb in milk of both species were higher than in plasma. However, a fast passage through the blood-milk barrier and a high storage of imidocarb were observed in the milk of ewes, whereas the drug concentrations were not as high nor was the extent of drug penetration from blood to milk as great in the milk of goats (AUCmilk 0–48/AUCplasma 0–48 = 2.5±0.45 and 1.26±0.27 in sheep and goat, respectively). Despite the differences in pharmacokinetic behavior, and considering the sensitivity of pathogens to imidocarb, the same dosage regimen can be used for clinical efficacy against Babesia spp. infection in both species. In contrast, the differences in depletion of imidocarb residue in milk and the large variability in mammary drug elimination found in goats suggests that great care should be taken in defining the withdrawal time in small ruminant dairy species.

Eprinomectin in dairy zebu Gobra cattle (Bos indicus): plasma kinetics and excretion in milk

The pharmacokinetics and mammary excretion of eprinomectin were determined in zebu Gobra following topical administration of 0.5 mg kg(-1). The kinetics of plasma and milk was analysed using a one-compartment model. The maximum plasma concentration of 8.83+/-2.15 ng ml(-1) occurred 1.30 days post-administration. The area under the plasma concentration-time curve was 30.63+/-5.56 ng day(-1) ml(-1) and the mean residence time was 3.38+/-0.60 days. Eprinomectin was detected in milk at the first sampling time and thereafter for at least 8 days. The systemic availability of eprinomectin was significantly lower than that for other breeds of cattle. Comparison of the milk and plasma data demonstrated the parallel disposition of the drug in the milk and plasma with a milk/plasma ratio of 0.094. The very low extent of mammary excretion supports the permitted use of eprinomectin in lactating zebu Gobra.

Pharmacokinetics, Urinary and Mammary Excretion of Ceftriaxone in Lactating Goats

The pharmacokinetic properties of ceftriaxone were investigated in 10 goats following a single intravenous (i.v.) and intramuscular (i.m.) administration of 20 mg kg(-1) body weight. After i.v. injection, ceftriaxone serum concentration-time curves were characteristic of a two-compartment open model. The distribution and elimination half-lives (t(1/2alpha), t(1/2beta)) were 0.12 and 1.44 h respectively. Following i.m. injection, peak serum concentration (C(max)) of 23.6 microg ml(-1) was attained at 0.70 h. The absorption and elimination half-lives (t(1/2ab), t(1/2el)) were 0.138 and 1.65 h respectively. The systemic bioavailability of the i.m. administration (F %) was 85%. Following i.v. and i.m. administration, the drug was excreted in high concentrations in urine for 24 h post-administration. The drug was detected at low concentrations in milk of lactating goats. A recommended dosage of 20 mg kg(-1) injected i.m. every 12 h could be expected to provide a therapeutic serum concentration exceeding the minimal inhibitory concentrations for different susceptible pathogens.

BIOAVAILABILITY AND MAMMARY EXCRETION OF BISPHENOL A IN SPRAGUE-DAWLEY RATS

This study reports the absolute oral bioavailability and mammary excretion of bisphenol A in rats. The oral bioavailability was determined after administration of relatively low iv (0.1 mg/kg) and oral (10 mg/kg) doses of bisphenol A to rats. After iv injection, serum levels of bisphenol A declined biexponentially, with the mean initial distribution and terminal elimination half-lives being 6.1 - 1.3 min and 52.5 - 2.4 min, respectively. The systemic clearance (Cl s ) and the steady-state volume of distribution ( V ss ) averaged 107.9 - 28.7 ml/min/kg and 5.6 - 2.4 L/kg, respectively. Upon oral administration, the maximum serum concentration ( C max ) and the time to reach the maximum concentration ( T max ) were 14.7 - 10.9 ng/ml and 0.2 - 0.2 h, respectively. The apparent terminal elimination half-life of bisphenol A (21.3 - 7.4 h) after oral administration was significantly longer than that after iv injection, indicating the flip-flop of the absorption and elimination rates. The absolute oral bioavailability of bisphenol A was low (5.3 - 2.1%). To determine the extent of mammary excretion, bisphenol A was given by simultaneous iv bolus injection plus infusion to steady state at low, medium, and high doses. The steady-state serum levels of bisphenol A were linearly increased with higher dosing rates. The systemic clearance (mean range, 119.2-154.1 ml/min/kg) remained unaltered over the dosing rate studied. The levels of bisphenol A in milk exceeded those in serum, with the steady-state milk to serum concentration ratio being 2.4-2.7.

Pharmacokinetics of eprinomectin in plasma and milk following topical administration to lactating dairy cattle

The pharmacokinetics and mammary excretion of eprinomectin were determined in cattle following topical administration at a dose rate of 0·5 mg kg–1. The kinetics of plasma and milk concentrations were analysed using a one-compartment model. The maximum plasma concentration of 43·76 ng ml–1occurred 2·02 days post administration, and the mean residence time was 4·16 days. Eprinomection was detected in the milk at the first sampling time and thereafter for at least 15 days. Comparison of the milk and plasma data demonstrated the parallel disposition of the drug in the milk and plasma with a milk / plasma concentration ratio of 0·102±0·048. The amount of drug recovered in the milk during this period was 0·109% ± 0·038 of the total administered dose. This very low extent of mammary excretion resulted in low concentrations of eprinomectin in milk. This supports the permitted use in lactating cattle, as the maximum level of residue in milk did not exceed the maximum acceptable limit of 30 ng ml–1.

Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase. (3). Foeto-placental Transfer and Mammary Excretion after Oral Administration in Rats.

NK-104 is a very potent competitive inhibitor of HMG-CoA reductase. In this study, the transfer of radioactivity into the fetus and milk were investigated in pregnant and lactating rats after a single oral administration of 14C-NK-104 at a dose of 1 mg/kg. Whole body autoradiograms of rats on the 18th day of gestation showed a low distribution of radioactivity to amniotic fluid and fetus. On the 13th and 18th day of gestation, the levels of radioactivity in the placenta tissue were less than those in the maternal plasma. Therefore little radioactivity was transferred into the fetus, accounting for less than 36% of that in maternal plasma. The radioactivity in the milk reached a maximum level at 6 hr after administration to the lactating rats on the 14th day after delivery, being seven times higher than that in the maternal plasma. Although the composition of radioactivity in the milk consisted mostly of the unchanged NK-104, its concentration was below the detection limit at 48 hr.

Placental Transfer and Mammary Excretion of 1-(Bis(4-fluorophenyl)-methyl)-4-(2,3,4-trimethoxybenzyl)piperazine Dihydrochloride(KB-2796) in Rats.

The placental transfer and mammary excretion of 1-[bis(4-fluorophenyl)-methyl]-4-(2, 3, 4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796) were studied in rats after oral administration of 14C-labeled KB-2796. 1. The whole-body autoradiograms after oral administration to rats on the 13th day of pregnancy showed that the radioactivity in the fetus was higher than that in the placenta. 2. The maximum levels of radioactivity in the fetus were reached at 1 hr after administration to rats on the 18th day of pregnancy. The elimination of radioactivity in the fetus was slower than that in maternal plasma. The levels of radioactivity in the fetus at 48 hr was about 4 times higher than that in the mater nal plasma. In the fetus, radioactivity in the liver and lung was relatively higher than in other tissues, and the radioactivity in the lung was increasing up to 96 hr after the administration. 3. The maximum levels of radioactivity in the milk reached at 6 hr after the administration to lactating rats. The concentration is 37 times higher than that in the plasma. Thereafter, the concentration in the milk declined with half-life of 12.3 hr by 48 hr after dosing. The elimination was parallel to the plasma level. 4. The main metabolites of KB-2796 in the maternal and fetal lung were bis(4-fluorophenyl)methylpiperazine (M6) and 4, 4'-difluorobenzophenone (M10). 5. The unchanged KB-2796 accounted for about 60% of total radioactivity in the milk. 1-[Bis (4-fluorophenyl) methyl]-4-(3, 4-dimethoxy-2-hydroxybenzyl) piperazine (M2) and M10 were detected as the main metabolites in the milk.

Residues of ethion in milk after intravenous, oral and dermal administration to goats

Mammary excretion and residues in milk of the organophosphorus insecticide ethion were studied in lactating goats after intravenous and oral administration of 14 C ethion and after dermal application.

Metabolic fate of Sodium 5-(acetylamino)-3,5-dideoxy-D-glycero-D-galacto-2-nonulosonate (KI-111). (II): Placental transfer and mammary excretion in rats.

Placental transfer and mammary excretion of radioactivity were investigated in pregnant rats and lactating rats after intravenous administration of 14C-labelled Sodium 5-(acetyl-amino)-3, 5-dideoxy-D-glycero-D-galacto-2-nonulosonat (KI-111).Placental transfer was investigated on day 13 and 19 of pregnancy by measurement of tissue level, and by whole body autoradiography(WARG) on day 19 of pregnancy. Five minutes after administration of KI-111, the radioactivity was observed in the all tissues and organs except the fetuses as revealed by the WARG. Regarding the tissue levels of KI-111 in day 13 and 19 pregnant rat, no radioactivity was detected in the fetuses within 1.5 hour after administration, though 24 hours after administration, small amount of radioactivity was de tected in the whole fetus of day 13 pregnant rat. No radioactivity was detected in the fetal organs 5 to 45 minutes after administration, however, small amount of radioactivity was detected in the fetal brain and fetal intestine in the day 19 pregnant rat during 1.5 to 24 hours after administration.Radioactivity excreted into the milk was determined on day 10 to 12 after parturition. The highest concentration of radioactivity in the milk was observed at 1.5 hour after administra tion, but the amount was small.

Isometamidium in goats: Disposition kinetics, mammary excretion and tissue residues

The pharmacokinetics of the antitrypanosomal drug isometamidium were studied in lactating goats after intravenous and intramuscular administration at a dose of 0·5 mg/kg body weight, in a crossover design at an interval of 6 weeks. Following intravenous administration, the half-life of the disappearance of the drug from plasma during the terminal phase was 3·2 h, and the mean residence time was 2·4 h. The apparent volume of distribution averaged 1·52 l/kg, and the mean total body clearance was 0·308 l/kg/h. After intramuscular administration, the absolute bioavailability was low, averaging 27%. This was consistent with a low mean maximum concentration of 24 ng/ml which occurred after 6 h. No drug was detectable (< 10 ng/ml) in milk samples collected over a period of 14 days following drug administration by either the intravenous or intramuscular route. In tissues analysed when the goats were killed 6 weeks after administration of the second dose, no drug was detectable (< 0·4 μg/g wet tissue) in the liver, kidney and muscle. However, at the injection site, drug concentrations varied from < 0·4 to 18·8 μg/g wet tissue.