Pharmacokinetics and pharmacodynamics in man of the dopamine antagonist ergot derivative,bromerguride

Summary The plasma levels and urinary excretion of the dopamine antagonist, bromerguride, were measured by radioimmunoassay in healthy male volunteers given 50 µg i.v. and oral doses of 1 and 2 mg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of bromerguride declined biphasically, with half-lives of 7 min and 1.2h. The total clearance was 32 ml·min^–1·kg^–1 and the apparent volume of distribution was 3.6 l/kg. The bioavailability of oral bromerguride was 29% after 1 mg and 25% after 2 mg. The drug was almost totally metabolized and less than 0.05% of the dose was excreted in urine in 24 h after oral administration. Plasma prolactin levels were increased in a dose-dependent manner for about 8 h. Side-effects were minimal, mainly being tiredness and headache in some of the volunteers.     

Pharmacokinetics and pharmacodynamics of the ergot derivative,transdihydrolisuride, in man

Summary Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 µg i.v. and oral doses of 200, 400 and 800 µg. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37±19 min. The total clearance was 38±27 ml/min/kg and the apparent volume of distribution was 1.3±0.4 l/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 µg the bioavailability was 20±25%, 31±24% and 48±26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66±15%, 75±11% and 80±7% after TDHL 200 µg, 400 µg and 800 µg. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 µg. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.     

Pharmacokinetics of a new histamine H2-receptor antagonist,Z-300, in rat and dog

1. The plasma level of Z-300 reached a maximum (C_max) at 30?min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a halflife of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3?mg/kg. At doses ranging from 3 to 30?mg/kg, C_max and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached C_max at 10?min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10?mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50?mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of α₁-acid glycoprotein (α₁-AG), because Z-300 bound more strongly to α₁-AG than to albumin.     

Pharmacokinetics of a new histamine H2-receptor antagonist, Z-300, in rat and dog.

1. The plasma level of Z-300 reached a maximum (Cmax) at 30 min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a half-life of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3 mg/kg. At doses ranging from 3 to 30 mg/kg, Cmax and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached Cmax at 10 min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10 mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50 mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of alpha1-acid glycoprotein (alpha1-AG), because Z-300 bound more strongly to alpha1-AG than to albumin.     

Pharmacokinetics of barnidipine hydrochloride,a new dihydropyridine calcium channel blocker,in the rat,dog and human

1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man.

2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0·6?h in the rat and 4·1?h in the dog. The blood clearance was 5·21/h/kg in the rat and 3·31/h/kg in the dog, and was comparable with hepatic blood flow in both species.

3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0·3-0·4?h in the rat and dog, 1·0–1·6?h in man). C_max and AUC rose non-linearly with increasing doses in all three species.

4. The absolute bioavailability was low (11–18% in the rat and 6–9% in the dog), suggesting a marked first-pass metabolism.     

Pharmacokinetics of cyanamide in dog and rat

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (E.C. 1.2.1.3) has been made in the beagle dog and Sprague-Dawley rat. Cyanamide plasma levels were determined by a sensitive high performance liquid chromatographic assay, specific for cyanamide. In the dog, i.v. administration of cyanamide at 1, 2 and 4 mg kg-1, produced a dose-dependent pharmacokinetic behaviour. Statistically significant changes were observed in plasma clearance values (12.6 to 19.7 mL kg-1 min-1), half life values (39 to 61 min) and mean residence times (50 to 79 min). Peak plasma concentrations, after oral administration of 4 mg kg-1 were achieved at 30 min and oral bioavailability was about 65%. In the rat after i.v. or oral administration, cyanamide (2 mg kg-1) had a half life of 30 min, a total plasma clearance of 117 mL kg-1 min-1 and a mean residence time of 26 min. Oral bioavailability was about 69%.     

Pharmacokinetics and metabolism of a 4'-methylthio derivative of propranolol in the dog

The purpose of this study was to examine the effect of a methylthio substituent in the metabolically most active position of propranolol, i.e. the 4'-position, on the pharmacokinetics and metabolism of this drug in the dog. The kinetics of 4'-methylthiopropranolol (MTP) were compared to those of propranolol following simultaneous iv doses of labeled drug and oral doses of unlabeled drug. MTP had a significantly larger volume of distribution and a longer half-life, and demonstrated a greater accumulation by red blood cells and cardiac conductile tissue than propranolol, effects which presumably are due to a higher lipophilicity of MTP. The greatest effect was on the oral clearance, which was substantially lower for MTP (1.6 vs. 5.5 liters/min) with an associated higher bioavailability (23.1 vs. 10.9%). Studies of MTP metabolism using radiolabeled drug showed that MTP, like propranolol, was eliminated entirely by metabolism. About 70% of the urinary radioactivity was extractable into ethyl acetate at pH 9.8 and pH 2.0. The extractable metabolites were separated by HPLC and identified by GC/MS, direct probe MS, and comparison with authentic compounds. Eleven metabolites were identified as sulfoxides and, in particular, sulfones of MTP and its N-dealkylated and subsequently deaminated glycollic and lactic acid metabolites. The nonextractable urinary radioactivity (30%) was isolated by DEAE-Sephadex chromatography and identified by HPLC/MS as four glucuronic acid conjugates. In contrast to propranolol, there was no evidence of aromatic carbon oxidation for MTP. These observations suggest that the markedly decreased oral clearance of MTP compared to propranolol is due to qualitatively altered metabolism from a highly efficient aromatic carbon oxidation for propranolol to a less efficient sulfur oxidation for MTP.     

Pharmacokinetics of droxicam in rat and dog

A study was made of the oral absorption of droxicam in the rat. Five minutes after administration of 1 mg/kg droxicam, only piroxicam levels (its active metabolite) were detected at the portal vein and caudal vena cava. The transformation of droxicam into piroxicam takes place in the gastrointestional tract. A pharmacokinetic test to compare the plasma levels of piroxicam obtained in rat and dog was then made after oral administration of droxicam and piroxicam. In both animal species the oral absorption of droxicam was not dose-related. However, droxicam given at therapeutic doses (0.2-0.3 mg/kg) was bioequivalent to piroxicam. The elimination half-life of piroxicam after oral administration of droxicam and piroxicam was 8 +/- 2 h in the male rat, 27 +/- 12 h in the female rat and 38 +/- 18 h in the male dog, whilst the half-life of oral absorption of piroxicam did not vary from one animal species to another. In the case of droxicam, however, this value was higher than that after oral administration of piroxicam, as a consequence of the process of transformation of droxicam into piroxicam. It is concluded that droxicam is a prodrug of piroxicam with a slower rate of absorption, but with the same bioavailability within the range of therapeutic doses.     

Pharmacokinetics and tissue distribution of the new gastrokinetic agent cisapride in rat, rabbit and dog

The plasma kinetics and tissue distribution of the gastrokinetic (+/-)-cis-4-amino-5-chloro-N-[1-(3-(4-fluorophenoxy)propyl]-3-methoxy-4- piperidinyl]-2-methoxybenzamide monohydrate (cisapride, R 51 619) have been studied in the rat, rabbit and dog. After intravenous administration to rats (5 mg/kg) and dogs (0.63 mg/kg) plasma level-time curves were adequately fitted to a two-compartmental model. The plasma clearance (ClT) and volume of distribution (Vdss) averaged 91 ml/min.kg and 4.7 l/kg in the rat and 4.2 ml/min.kg and 0.82 l/kg in the dog, respectively. Following oral administration, cisapride was rapidly and almost completely absorbed from the gastrointestinal tract in rats and rabbits. The absorption was somewhat slower in the dog. In male rats the plasma radioactivity was mainly due to metabolites, unaltered cisapride representing on average 10% of the total radioactivity. A markedly larger proportion of the parent drug was seen in female rats. Linear plasma kinetics were observed for cisapride in the dose range of 10 to 160 mg/kg. Similarly in the dog, linearity was observed after oral administration in the range of 0.31 to 10 mg/kg. The plasma kinetics remained unaltered on repeated oral doses of 10 mg/kg to rats and subchronic intravenous administration at 0.63 mg/kg to dogs. Compared with intravenous administration, the absolute bioavailability of oral cisapride was 23% in rats and 53% in the dog for the drug given in solution. The terminal plasma half-life of cisapride was about 1-2 h in the rat and about 4-10 h in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of a new antitumor 3-arylisoquinoline derivative, CWJ-a-5

The lungs are useful for administration of macromolecules, which are poorly absorbed from the intestine. In the present study, we prepared several dry powder formulations of insulin using a spray drying technique to examine the effect of additives on insulin absorption. The bioavailability of insulin was estimated from the change in the plasma glucose level. The bioavailability of insulin from dry powder with no additive exceeded that obtained from pH 7.4 solution. The absolute bioavailability of insulin administered as a solution with 1.4 mg/dose of bacitracin or 1.0 mg/dose of Span 85 was almost 100%. The bioavailability of dry powder with 0.42 mg/dose of bacitracin was 20% that of the solution with 1.4 mg/dose of bacitracin. The insulin dry powder with 0.21 mg/dose of Span 85 showed a bioavailability less than that for the insulin solution with 0.1 mg/dose of Span 85. Bacitracin and Span 85 were not as effective in dry powder as in solution in the present study. While citric acid was more effective in dry powder that in solution to increase the hypoglycemic effect. The pH 5.0 and pH 3.0 solutions containing 0.19 mg of citric acid in 0.1 ml showed absolute bioavailabilities of 43% and 57%, respectively, while the bioavailabilities for dry powders containing 0.025 and 0.036 mg/dose citric acid were 42% and 53%, respectively. In addition, the hypoglycemic effect of dry powders continued for a longer period and remained at 240 min with the dry powders, while it disappeared at 180 min with the solutions. When the insulin dry powder containing 0.036 mg/dose of citric acid was administered, the lactate dehydrogenase activity, a sensitive indicator of acute toxicity to lung cells, in bronchoalveolar lavage was as low as that for saline administration, suggesting citric acid is a safe additive. Thus, citric acid appears to be a safe and potent absorption enhancer for insulin in dry powder.     

Pharmacokinetics and metabolism of gabapentin in rat, dog and man

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, G? 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.     

Pharmacokinetics of iododoxorubicin in the rat, dog, and monkey.

The pharmacokinetics of iododoxorubicin (I-DOX) have been studied after single dose administration in the rat (iv and po), dog (iv and po), and monkey (iv). Plasma levels and amounts in urine were monitored by HPLC for both I-DOX and its biologically active metabolite, iododoxorubicinol (I-DOXOL). Plasma levels of I-DOX after iv administration could be described by a three-exponential curve with extremely fast initial phase. Terminal elimination half-lives of I-DOX were similar, 6-7 hr, in all three species. Body weight-normalized clearance (CL) and distribution volumes (Vd) of I-DOX were lower in the dog, but were similar in rat and monkey. The pharmacokinetic parameters also implied metabolic differences between species. Mean I-DOXOL/I-DOX AUC ratios were 0.02, 0.47, and 0.58, respectively, in rat, dog, and monkey, values considerably lower than reported in human studies. I-DOXOL remained slightly longer in the body than I-DOX, as seen both from terminal half-lives (9-11 hr) and mean residence times. In all species, renal excretion was virtually negligible: the amount of I-DOX + I-DOXOL in urine was less than 2% of dose. Mean bioavailabilities of I-DOX were 0.23 and 0.46 in rat and dog, respectively, and, in the latter, about half of I-DOXOL formation occurred during or before the first pass.     

Pharmacokinetics of a new antihypertensive pyrrolyl pyridazinamine (MDL-899) in the rat and the dog

The pharmacokinetics of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new antihypertensive agent, was studied in rats and dogs. The 14C-labelled compound was synthesized by a microscale procedure with 45% chemical yield and 98% radiochemical purity. In both animal species, MDL-899 was rapidly absorbed from the gastro-intestinal tract, achieving peak plasma levels in 0.5-2 h. The ratio between the plasma concentrations of 14C and of unchanged MDL-899 indicates rapid metabolic transformation and, especially in the rat, a marked first-pass effect. MDL-899 binds to serum proteins with a very low affinity and rapidly enters the tissue compartment, with large distribution volumes (1.6 l/kg rat, 2.0 l/kg dog). Target tissues in the rat were the liver, kidneys, adrenals, lungs, ovaries, uterus and the arterial walls, which constitute a deep-compartment. The plasma half-life of unchanged MDL-899 was 0.5 h in the rat and 1.4 h in the dog, while the terminal half-lives for total radioactivity were much longer (two elimination phases). Within the range of doses tested (1 and 40 mg/kg) there is evidence of non-linear kinetics (dog). The plasma kinetics profiles of both MDL-899 and 14C were the same in both males and females (rat). In both rats and dogs, elimination of the test dose was preferentially via the kidneys, as metabolites. The time course of the pharmacological response seems to be correlated to the kinetics of the active species in deep-compartment(s) rather than to the plasma concentration.     

Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat, dog and human

1. UK-224,671 is a sulphamide-containing NK2 antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was < 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK-224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [14C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.     

Pharmacokinetics and tissue distribution of ketanserin in rat, rabbit and dog

The plasma kinetics and tissue distribution of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468) were studied in the rat, rabbit and dog. The studies were performed utilizing 3H- and 14C-labelled ketanserin and appropriate techniques to measure levels of radioactivity, unchanged drug and a major metabolite ketanserin-ol in plasma and tissues. Following intravenous administration to male rats and dogs (10 mg/kg), plasma levels could be described by a two-compartment model. The plasma clearance (C1) averaged 3.8 and 19.2 ml/min/kg and the volume of distribution (Vdss) 0.67 and 4.7 l/kg in male rats and in dogs, respectively. Following oral administration (10-40 mg/kg), ketanserin was rapidly and completely absorbed in all species studied. The absolute bioavailability of oral ketanserin was more than 80% in both rats and dogs. Due to the high clearance of the metabolites in rats, ketanserin was the main component of the plasma radioactivity. In dogs, the fraction of the metabolite ketanserin-ol was more pronounced than that of ketanserin. The apparent elimination half-life of ketanserin was 1.5 h in rabbits, 2-5 h in rats and 3-15 in dogs. The pharmacokinetics of ketanserin were dose-related after single and chronic intravenous and oral dosing. Distribution studies in rats after intravenous and oral administration (10 mg/kg) demonstrated an almost immediate equilibrium between plasma and tissues, resulting in slightly higher tissue than plasma concentrations in the well perfused tissues, and similar or slightly lower levels in the remaining tissues. Ketanserin was the main component of tissue radioactivity. The drug crossed the blood-brain barrier only to a slight extent, brain levels of the unchanged drug being similar to the free fraction in plasma. Ketanserin disappeared from tissues with a similar half-life to that in plasma. On repeated dosing, a small fraction of metabolites was more slowly eliminated. The excretion of the urinary and faecal metabolites after repeated dosing was very similar to that after a single dose. Placental transfer of ketanserin in the rat was limited. On average 0.3% of the maternal radioactive dose, preferentially metabolites, was recovered from the combined foetuses. In dogs orally treated with doses of up to 40 mg/kg/d for 12 months, no undue accumulation or retention of ketanserin or ketanserin-ol was found in any tissue. In lactating dogs orally dosed at 10 mg/kg, preferentially metabolites were excreted in the milk. Concentrations of ketanserin and ketanserin-ol in the milk were respectively 2 and 4 times higher than plasma levels.     

Pharmacokinetics and metabolism of a sulphamide NK2 antagonist in rat,dog and human

1. UK-224,671 is a sulphamide-containing NK₂ antagonist with moderate lipophilicity and basicity. 2. The physicochemical properties of UK-224,671 are reflected in its pharmacokinetics following intravenous (i.v.) administration. The compound partitioned extensively into red blood cells in all species examined and the blood clearance was moderate to low with respect to liver blood flow and distribution into tissues was extensive. 3. UK-224,671 exhibited species differences in oral bioavailability. In dog, the compound exhibited moderate bioavailability (55%), whereas in rat and man oral bioavailability was &lt; 10%. 4. In rat and dog, the major excreted form after i.v. administration was unchanged UK224,671 in both urine and faeces. In addition, of three metabolites observed, the most abundant was the N-descyclopropylmethyl (UK-280,045). 5. The profile of radioactivity in rat following oral administration of [¹⁴C]-UK-224,671 was not consistent with a 10% absorbed compound with 40% of the dose present as metabolites. This suggests that the low bioavailability of UK-224,671 in rat is due to a combination of moderate intestinal permeability and extensive first-pass metabolism by the gut and does not result from poor gastrointestinal absorption per se.     

Pharmacokinetics and metabolism of dofetilide in mouse, rat, dog and man.

1. Pharmacokinetics of dofetilide were studied in man, dog, rat and mouse after single i.v. and oral doses of dofetilide or 14C-dofetilide. 2. Dofetilide was absorbed completely in all species. Low metabolic clearance in man resulted in complete bioavailability following oral administration. Higher metabolic clearance in rodents, and to a lesser extent dogs, resulted in decreased bioavailability because of first-pass metabolism. 3. Following i.v. administration, the volume of distribution showed only moderate variation in all species (2.8-6.3 l/kg). High plasma clearance in rodents resulted in short half-life values (mouse 0.32, male rat 0.5 and female rat 1.2 h), whilst lower clearance in dog and man gave longer terminal elimination half-lives (4.6 and 7.6 h respectively). 4. After single i.v. doses of 14C-dofetilide, unchanged drug was the major component excreted in urine of all species with several metabolites also present. 5. Metabolites identified in urine from all species were formed by N-oxidation or N-dealkylation of the tertiary nitrogen atom of dofetilide. 6. After oral and i.v. administration of 14C-dofetilide to man, parent compound was the only detectable component present in plasma and represented 75% of plasma radioactivity. No single metabolite accounted for greater than 5% of plasma radioactivity.     

Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.