Metronidazole: pharmacokinetic observations in severely ill patients

Single and multiple dose pharmacokinetics of metronidazole and its two major metabolites were studied in ten patients. Patients with hepatic insufficiency had longer average serum half-life of metronidazole (11.2 h) than individuals with normal liver and kidney function (5.9 h) or isolated moderate renal impairment (6.5 h). Patients with hepatic disorder presented larger areas under the serum concentration curve, lower serum clearances and a tendency to more rapidly rising trough values of metronidazole. In patients with renal insufficiency trough values of the hydroxy metabolite seemed to rise faster and serum half-life was prolonged. The acetic acid metabolite was detected in serum of all patients with renal dysfunction but only in half of those with normal renal function and then at lower levels. A reduced 24-h total urinary recovery of metronidazole among patients with renal disorder was explained by a decreased excretion of hydroxy metabolite. The kinetics of metronidazole itself seem not to be influenced by renal impairment while the elimination rate of metabolites is reduced. The decreased clearance of the drug in patients with hepatic dysfunction makes a dose reduction in this patient group advisable.     

Use of High-Pressure Liquid Chromatography to Determine Plasma Levels of Metronidazole and Metabolites After Intravenous Administration

A rapid and sensitive high-pressure liquid chromatography assay for metronidazole and its two principle metabolites, 1-(2-hydroxyethyl-2-hydroxymethyl)-5-nitro-imidazole [hydroxy metabolite] and 1-acetic acid-2-methyl-5-metronidazole [acid metabolite], was developed. The retention times observed were 5.7, 3.3, and 4.5 min, respectively. A reverse-phase muC(18) Bondapak column using a solvent system of methanol, acetonitrile, and 0.005 M pH 4 potassium dihydrogen phosphate (4:3:93, vol/vol) was used to achieve separation of the three compounds. Patients receiving metronidazole therapy were given a loading dose of 13.6 mg of drug per kg intravenously over 1 h, followed by a maintenance dose of 1.43 mg/kg per h. The range of metronidazole concentrations observed was 6.8 to 47.5 mug/ml. These levels are well above the minimal inhibitory concentrations of most clinically significant anaerobic bacteria including Bacteroides fragilis. Little of the acid metabolite was observed in the plasma. The concentration of hydroxy metabolite ranged from 1.6 to 16 mug/ml. The latter may represent an additional source of antimicrobial activity since the hydroxy metabolite has approximately 30% the biological activity of metronidazole.     

Pharmacokinetics and metabolism of 14C-tinidazole in humans

Following intravenous infusion of 800 mg of 14C-tinidazole during 30 min to two human subjects, a mean of 44% of the dose was excreted in urine during the first 24 h, increasing to 63% of the dose during five days: 12% of the dose was excreted in the faeces, indicating the possible involvement of biliary excretion and other secretory processes in the disposition of tinidazole. At 6 min after the end of the infusion, the mean plasma tinidazole concentration was 12 mg/l. Tinidazole was a major component in 0-120 h urine (about 32% of urinary 14C): the major metabolite in the 0-12 h urine examined was ethyl 2-(5-hydroxy-2-methyl-4-nitro-1-imidazolyl)ethyl sulphone (about 30% urinary 14C), the product of hydroxylation and nitro-group migration. These compounds were also present in the faeces. A minor urinary metabolite was 2-hydroxymethyltinidazole (about 9% urinary 14C), which was also present in plasma. The mean pharmacokinetic parameters obtained for tinidazole were similar to those reported in the literature; total clearance 51 ml/min, renal clearance 10 ml/min, volume of distribution 501 and half-life 11.6 h.     

Susceptibility of Mobiluncus species to 23 antimicrobial agents and 15 other compounds.

The susceptibility of 12 strains of Mobiluncus curtisii and 10 strains of M. mulieris to 23 antimicrobial agents and 15 other compounds was determined. All strains were susceptible to chloramphenicol, clindamycin, rifampin, tobramycin, vancomycin, virginiamycin, and all beta-lactam antibiotics tested, including imipenem. One strain of M. mulieris was resistant to erythromycin and josamycin. All were resistant to colistin, cycloserine, nalidixic acid, and neomycin. Tetracycline had variable activity. All M. curtisii strains were resistant to metronidazole and its hydroxy metabolite. Of 10 M. mulieris strains, 5 were resistant to metronidazole and 2 were resistant to its hydroxy metabolite. All 12 M. curtisii and 1 of 10 M. mulieris strains were resistant to tinidazole. M. curtisii and M. mulieris produced two mutually exclusive clusters of MICs when tested against ampicillin, cefoxitin, cephalothin, moxalactam, alizarin red, Evans blue, and sodium fluoride. Gardnerella vaginalis was more susceptible to Nile blue A than was either M. curtisii or M. mulieris. Clindamycin and imipenem may be useful agents in the therapy of metronidazole-resistant bacterial vaginosis. Metronidazole, tinidazole, and Nile blue A may be of value in the development of a selective agar for Mobiluncus species.     

In vitro activities of metronidazole and its hydroxy metabolite against Bacteroides spp.

Metronidazole is metabolized to two major oxidative products: an acid metabolite and a hydroxy metabolite. While the activity of the acid metabolite is negligible, the activity of the hydroxy metabolite is approximately 65% of the activity of the parent drug. Pharmacokinetic studies of metronidazole and its hydroxy metabolite have shown that the MICs of both compounds remain above the MICs for most anaerobic organisms over an 8-h dosing interval. By a checkerboard assay, the combined activities of metronidazole and the hydroxy metabolite were examined against 4 quality control strains of Bacteroides species. Macrobroth tube dilutions were set up with Wilkins-Chalgren broth. Serial twofold dilutions of each agent were performed to achieve final concentrations ranging from 0.06 to 4.0 micrograms/ml. The MICs for Bacteroides fragilis and B. distasonis were 1.0 microgram/ml for both parent drug and metabolite. For B. thetaiotamicron and B. ovatus, the MICs of metronidazole and the hydroxy metabolite were 1.0 and 2.0 micrograms/ml, respectively. Synergy was determined by calculating the fractional inhibitory concentration (FIC) index. The interpretative criteria for the FIC index were as follows: synergy, FIC < or = 0.5; partial synergy, 0.51 to 0.75; indifference, FIC 0.76 to 4.0; and antagonism, FIC > 4.0. Partial synergy was observed for the four anaerobes tested, with FIC indices ranging from 0.63 to 0.75. On the basis of this data, in vitro susceptibilities to agents such as metronidazole may ultimately require reevaluation to account for active metabolites.     

In-vitro and in-vivo activity of metronidazole against Gardnerella vaginalis, Bacteroides spp. and Mobiluncus spp. in bacterial vaginosis

An open, randomized, culture-controlled clinical study was designed to compare the efficacy of a single 2 g dose of metronidazole (Elyzol) with standard 7-day therapy in the treatment of bacterial vaginosis (BV). Forty-one of 47 (87%) patients given the single dose and 30 of 33 (91%) given the 7-day treatment were found to be cured seven days after treatment. At final assessment, 24 of 34 (71%) patients given the single dose and 22 of 28 (79%) given the 7-day treatment remained cured. The two regimes were equally efficaceous in eradicating Gardnerella vaginalis, Bacteroides spp. and Mobiluncus spp. (anaerobic curved rods) from vaginal specimens from patients with BV. The in-vitro activity of metronidazole and its hydroxy metabolite was determined for 11 strains of Gard. vaginalis, 17 strains of Bacteroides spp. and 14 strains of Mobiluncus spp. which had been isolated from patients prior to treatment. The MIC of metronidazole against Gard. vaginalis varied between 2 and greater than or equal to 128 mg/l (median MIC 32 mg/l), but the hydroxy metabolite showed a markedly increased activity against eight of the strains tested (median MIC 4 mg/l). The MIC of metronidazole against the Mobiluncus spp. varied between 0.5 and greater than or equal to 128 mg/l (median MIC 16 mg/l) and the hydroxy metabolite showed little increased activity (median MIC also 16 mg/l). The Bacteroides organisms were highly susceptible to metronidazole and to the hydroxy metabolite, each having a median MIC of 1 mg/l.     

Comparison of 2 g single dose of metronidazole, nimorazole and tinidazole in the treatment of vaginitis associated with Gardnerella vaginalis

Vaginitis associated with the presence of Gardnerella vaginalis (confirmed by culture) was treated either with metronidazole or with one of the two nitroimidazole derivatives; nimorazole or tinidazole, as a single oral 2 g dose. Eighty-two patients were treated with metronidazole, 100 with nimorazole and 98 with tinidazole. The cure rates were 79%, 88% and 92% with metronidazole, nimorazole and tinidazole respectively. Therefore we recommend a single dose of 2 g of any of these three drugs in the treatment of such infection.     

Concentrations of metronidazole and tinidazole in abdominal tissues after a single intravenous infusion and repetitive oral administration

Concentrations of metronidazole and tinidazole in serum and abdominal tissues were determined after a single 500-mg intravenous infusion or after a 5-day oral dosage of 500 mg three times daily in groups of 10 patients each. In the patients who got the single infusions, the concentrations in tissues (except fat) reached almost the serum levels 10 min after the infusion. At 24 h, the tinidazole concentrations in serum averaged 3.2 micrograms/ml and those of metronidazole 1.3 micrograms/ml. In the patients who got the 5-day oral dosages, the steady-state levels of tinidazole in both serum and tissues were twice as high as those of metronidazole.     

Single-dose tinidazole for the treatment of giardiasis.

Sixty-three expatriate residents and travellers in Bangladesh, infected with Giardia lamblia, participated in two studies to compare the therapeutic efficacy of tinidazole and metronidazole. In the first trial 33 randomly selected patients were treated with tinidazole (50 mg/kg of body weight to a maximum of 2 g) or metronidazole (60 mg/kg of body weight to a maximum of 2.4 g) in a single oral dose. Patients were followed for 4 weeks after the end of therapy for the presence of G. lamblia in their stools. Sixteen (94%) of 17 patients receiving tinidazole were free of G. lamblia during that period, compared to only 9 (56%) of 16 patients who had received metronidazole (P less than 0.02). In the second trial patients were randomly allocated to a treatment schedule of either metronidazole as a single dose on 3 successive days (50 mg/kg of body weight to a maximum of 2 g daily) or tinidazole as a single oral dose (50 mg/kg of body weight to a maximum of 2 g). All 15 patients treated with tinidazole and 14 (93%) of 15 patients treated with metronidazole were free of G. lamblia during the 4-week follow-up period. A single oral dose of tinidazole is a highly effective treatment for giardiasis and is equal in efficacy to a 3-day therapy with metronidazole.     

A comparison of a short course of single daily dosage therapy of tinidazole with metronidazole in intestinal amoebiasis

Sixty patients with symptomatic intestinal amoebiasis were treated for 3 days with a single dose of 2 g of either tinidazole or metronidazole respectively by random order. Tinidazole cured 90% of patients (27/30) an metronidazole cured 53.3% of patients (16/30). The difference was significant (p less than 0-01). Mild side-effect were reported by 26-7% of patients (8/30) in the tinidazole group as compared to mild to moderated side-effects reported by 53.3% of patients (16/30) in the metronidazole group. The difference was statistically significant (p less than 0-05). As the average patient has only a limited understanding and toleration of extended treatment courses, the advantages of a short course employing a single daily dose are obvious. With such a regimen, tinidazole was found to be superior to metronidazole in intestinal amoebiasis.     

Metabolism and disposition of amifloxacin in laboratory animals.

Sprague-Dawley rats received [14C]amifloxacin mesylate either orally or intravenously at 20 mg (base equivalent) per kg. Blood radioactivity peaked at 0.5 h after oral administration and was equivalent to 7.54 micrograms/ml for males and 6.73 micrograms/ml for females. After intravenous administration to rats, 52.5% of the dose was recovered in the urine of males and 45.3% in the urine of females within 72 h. The corresponding values after oral administration were 50.8% for males and 37.2% for females. The remainder of the dose was recovered in the feces. After intravenous administration of [14C]amifloxacin mesylate at 10 mg (base equivalent) per kg to female rhesus monkeys, 80.3% of the radioactivity was excreted in the urine at 24 h. The apparent first-order terminal elimination half-life of intact amifloxacin in plasma was 2.3 h; radioactivity in plasma was eliminated more slowly. Male rats excreted 26.2% of the dose in the urine as amifloxacin and 17.8% as the piperazinyl-N-oxide derivative of amifloxacin after intravenous administration. The corresponding amounts for female rats were 29.0% as amifloxacin and 7.8% as the piperazinyl-N-oxide metabolite. Similar excretion profiles were observed after oral administration. After intravenous administration, female monkeys excreted 54.5% of the dose in the urine as amifloxacin, 12.9% as the piperazinyl-N-desmethyl metabolite, and 5.6% as the piperazinyl-N-oxide during the first 12 h. In contrast, there was no evidence of the piperazinyl-N-desmethyl metabolite in rats.     

Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route

Serum kinetics of metronidazole and tinidazole were compared in four separate randomized crossover studies. Single doses of each drug were given to healthy volunteers through intravenous infusion (500 mg over 20 min, six persons), by mouth (500 mg, nine persons), by rectum (1,000 mg, six persons), or intravaginally (500 mg, six persons). Concentrations of the unchanged drugs in serum, measured by high-pressure liquid chromatography, were similar after oral and intravenous administration, with mean peaks of 9.0 and 9.4 micrograms/ml for metronidazole and 7.5 and 10.1 micrograms/ml for tinidazole. Concentrations of tinidazole were significantly higher than those of metronidazole from 4 h onwards after intravenous infusion, and from 3 h onwards after administration by mouth. After rectal administrations, a significant difference was seen only at 48 h. After vaginal dosing, however, concentrations of metronidazole were significantly higher than those of tinidazole between 1.5 and 12 h. Bioavailability of either drug, calculated according to the formula (area under the curve for oral administration)/(area under the curve for infusion), was practically complete after oral administration and was poorer after rectal and especially vaginal administration. Whenever the parameters were calculable, the elimination half-life of tinidazole (range of means, 14.0 to 14.7 h) was significantly longer and total clearance (40.3 to 47.6 ml/min) was lower than the corresponding values of metronidazole (7.9 to 8.8 h and 71.8 to 80.1 ml/min, respectively).     

Pharmacokinetics of metronidazole and its metabolites in reduced renal function

The pharmacokinetics of metronidazole (M), hydroxymetronidazole (OH-M), and acetylhydroxymetronidazole (A-M) were determined after a single intravenous dose of 0.5 g metronidazole. This was administered as an intravenous infusion during 30 min to 10 healthy volunteers and 24 patients with varying degrees of reduced renal function. Serum and urine concentrations were assayed by high-pressure liquid chromatography. The peak concentrations of the hydroxymetabolite appeared within an hour in the healthy volunteers and after a mean of 2.6 h (range 0.5-12.5 h) in the patients with reduced renal function. Analogously, the peak of the acetylmetabolite appeared later, at an average of 6.9 h and a range of 0.5-36.5 h. A-M was not observed in serum of the healthy subjects nor in 6 of the patients, but was recovered in urine of all subjects. The serum concentrations of M and OH-M were detectable throughout the 48 h monitored. Total urinary recovery in healthy subjects was 108.0% of the dose. This breaks down to 18.4% metronidazole, 62.4% OH-M, and 27.2% A-M. In the patients with reduced renal function, the relative contribution of A-M is higher than that of the other two products. The serum half-life of metronidazole was 7.1 in the healthy subjects and similar in reduced renal function (range 3.5-12.4 h). The serum half-life of OH-M was 18.0 h in the healthy and ranged 9.6-85.5 h in renal impairment. Long half-life values of 8.5-36.5 h were observed for A-M. Accumulation of OH-M and particularly of A-M was marked in reduced renal function. In the normal healthy volunteers, the coefficient of the steady-state distribution volume averaged 0.404 liter/kg of the terminal phase distribution volume 0.542 liter/kg, and the total body clearance 3.1 liter/h. The total body clearance of the unchanged compound was not influenced by reduced renal function.     

Pharmacokinetics of cefotaxime and desacetyl-cefotaxime in cirrhosis of the liver

In 9 patients with advanced hepatic cirrhosis and a normal serum creatinine concentration, the pharmacokinetics of cefotaxime (CTX) and its desacetyl metabolite (DACM) were examined in serum and urine after intravenous administration of 2.0 g CTX. The peak serum levels were 130.3 +/- 33.9 and 8.5 +/- 4.6 mg/l for CTX and DACM, respectively. T50% beta was calculated to be 138.1 min (69.3-245.8 min) for CTX. The approximation of the terminal half-life of DACM revealed a prolongation which exceeded 10 h. Accordingly, the AUC amounted to 255.3 +/- 92.0 and 151.9 h X mg/l, respectively. Within 24 h, 62.9% was eliminated in urine as CTX and 19.4% as DACM. The total clearance of CTX was reduced to 164.3 ml/min (58.3-296.6 ml/min), but the renal clearance was only moderately decreased to 90.0 ml/min (24.1-169.3 ml/min). These altered kinetics can be explained by altered metabolic function of the liver as well as by cirrhosis-linked alterations of renal elimination mechanisms.     

Serum and Urinary Concentrations of Cyclacillin in Humans

Cyclacillin is a semisynthetic penicillin produced from the penicillin nucleus (6-aminopenicillanic acid) by acylation with 1-aminohexanecarboxylic acid. The absorption and excretion characteristics of cyclacillin were defined in one completely randomized and three three-way crossover experiments. Mean peak serum cyclacillin levels appeared earlier and were fivefold higher than those obtained with equal doses of ampicillin. High serum cyclacillin concentrations were reached at 0.5 h and by 2 h were lower than ampicillin. Serum ampicillin concentrations peaked at 1.5 h, remaining slightly higher than those for cyclacillin for the next 4.5 h. The mean area for the cyclacillin curve was significantly superior to either of the ampicillin formulations. Mean serum concentrations of cyclacillin exhibited a smooth dose-response, approximately doubling in each instance as the dose was doubled from 250 to 500 and from 500 to 1,000 mg. High concentrations of cyclacillin were also demonstrated in urine. Neither ratio of drug to metabolite in the urine nor the percent of excretion was significantly affected by the dose level. Sixty-seven percent of the drug was excreted unchanged, and 17% was excreted as penicilloic acid, with most of the excretion occurring within 6 h of administration. In subjects given 500 mg of cyclacillin (four times daily) for 6 days, 2% of the drug was excreted as 1-aminocyclohexanecarboxylic acid, and approximately 55% (24 to 91%) was unchanged. Neither formation nor excretion of the former was sex dependent.     

New metabolic and pharmacokinetic characteristics of thiocolchicoside and its active metabolite in healthy humans

Thiocolchicoside (TCC) has been prescribed for several years as a muscle relaxant drug, but its pharmacokinetic (PK) profile and metabolism still remain largely unknown. Therefore, we re-investigated its metabolism and PK, and we assessed the muscle relaxant properties of its metabolites. After oral administration of 8 mg (a therapeutic dose) of 14C-labelled TCC to healthy volunteers, we found no detectable TCC in plasma, urine or faeces. On the other hand, the aglycone derivative obtained after de-glycosylation of TCC (M2) was observed and, in addition, we identified, as the major circulating metabolic entity, 3-O-glucuronidated aglycone (M1) obtained after glucuro-conjugation of M2. One hour after oral administration, M1 plus M2 accounted for more than 75% of the circulating total radioactivity. The pharmacological activity of these metabolites was assessed using a rat model, the muscle relaxant activity of M1 was similar to that of TCC whereas M2 was devoid of any activity. Subsequently, to investigate the PK profile of TCC in human PK studies, we developed and validated a specific bioanalytical method that combines liquid chromatography and ultraviolet detection to assay both active entities. After oral administration, TCC was not quantifiable with an lower limit of quantification set at 1 ng/mL, whereas its active metabolite M1 was detected. M1 appeared rapidly in plasma (tmax=1 h) and was eliminated with an apparent terminal half-life of 7.3 h. In contrast, after intramuscular administration both active entities (TCC and M1) were present; TCC was rapidly absorbed (tmax=0.4 h) and eliminated with an apparent terminal half-life of 1.5 h. M1 concentration peaked at 5 h and this metabolite was eliminated with an apparent terminal half-life of 8.6 h. As TCC and M1 present an equipotent pharmacological activity, the relative oral pharmacological bioavailability of TCC vs. intramuscular administration was calculated and represented 25%. Therefore, to correctly investigate the PK and bioequivalence of TCC, the biological samples obtained must be assayed with a bioanalytical method able to specifically analyse TCC and its active metabolite M1.     

Activity of metronidazole and its hydroxy and acid metabolites against clinical isolates of anaerobic bacteria.

Susceptibility of clinical isolates of anaerobic bacteria to metronidazole and its two oxidation products, 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (the "alcohol" metabolite) and 2-methyl-5-nitroimidazole-1-acetic acid (the "acid" metabolite), were determined by the agar dilution technique. Results disclosed that the alcohol metabolite, although less active than metronidazole, inhibited the organisms tested at levels considered susceptible for metronidazole. The acid metabolite was less active, not inhibiting the organisms at levels within the susceptible range. In other studies, mixtures of known concentrations of metronidazole and the metabolites were assayed in a bioassay system used to measure metronidazole levels. These studies showed that the bioassay will measure metronidazole or the alcohol metabolite; the acid metabolite is not measured at levels achieved in clinical specimens. Since the activity of the alcohol metabolite is comparable to that of metronidazole, we feel that microbiological assays can be used for therapeutic monitoring of metronidazole levels in clinical situations.     

Comparative pharmacokinetic studies of ornidazole and metronidazole in man.

Pharmacokinetic characteristics of ornidazole and metronidazole were compared in man. Both drugs were labelled with 14C in the imidazole ring at position 2. Four healthy volunteers were given an oral dose of 750 mg of one of the drugs, followed 2--4 weeks later by the same dose of the other. The same technique for determining the unchanged compound was used for both drugs. Results may be summarized as follows: mean peak concentrations in the plasma of 10.9 mug/ml for ornidazole and of 12.3 mug/ml for metronidazole were reached 2--4 h and 30--60 min after administration, respectively; both drugs showed the same volume of distribution. Their binding to human plasma proteins was less than 15%; the mean half-life of elimination from the plasma was 14.4 h for ornidazole and 8.4 h for metronidazole; the mean radioactivity recovered from the urine and faeces during the first 5 days was 85% of the dose for ornidazole and 91% for metronidazole, the major proportion in each case being excreted in the urine; the radioactivity found in the faeces was 22.1% of the dose for ornidazole and 13.9% for metronidazole.     

Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study

Abacavir (1592U89) ((-)-(1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene- 1-m ethanol) is a 2'-deoxyguanosine analogue with potent activity against human immunodeficiency virus (HIV) type 1. To determine the metabolic profile, routes of elimination, and total recovery of abacavir and metabolites in humans, we undertook a phase I mass balance study in which six HIV-infected male volunteers ingested a single 600-mg oral dose of abacavir including 100 microCi of [(14)C]abacavir. The metabolic disposition of the drug was determined through analyses of whole-blood, plasma, urine, and stool samples, collected for a period of up to 10 days postdosing, and of cerebrospinal fluid (CSF), collected up to 6 h postdosing. The radioactivity from abacavir and its two major metabolites, a 5'-carboxylate (2269W93) and a 5'-glucuronide (361W94), accounted for the majority (92%) of radioactivity detected in plasma. Virtually all of the administered dose of radioactivity (99%) was recovered, with 83% eliminated in urine and 16% eliminated in feces. Of the 83% radioactivity dose eliminated in the urine, 36% was identified as 361W94, 30% was identified as 2269W93, and 1.2% was identified as abacavir; the remaining 15.8% was attributed to numerous trace metabolites, of which <1% of the administered radioactivity was 1144U88, a minor metabolite. The peak concentration of abacavir in CSF ranged from 0.6 to 1.4 microg/ml, which is 8 to 20 times the mean 50% inhibitory concentration for HIV clinical isolates in vitro (0.07 microg/ml). In conclusion, the main route of elimination for oral abacavir in humans is metabolism, with <2% of a dose recovered in urine as unchanged drug. The main route of metabolite excretion is renal, with 83% of a dose recovered in urine. Two major metabolites, the 5'-carboxylate and the 5'-glucuronide, were identified in urine and, combined, accounted for 66% of the dose. Abacavir showed significant penetration into CSF.     

Absorption, disposition and preliminary metabolic pathway of 14C-rifabutin in animals and man

14C-Rifabutin was given orally to rats, rabbits and monkeys at a dose of 25 mg/kg and to healthy volunteers at a dose of 270 mg. Radioactivity was eliminated by both the renal and faecal routes in all species, with a predominance of the renal route in man and monkeys (50.19% and 46.73% of the dose, respectively, in urine at 96 h), whereas in rats and rabbits a slight predominance of faecal excretion was observed (48.09% and 45.01% of the dose, respectively, at 96 h in faeces; 42.22% and 36.37% in urine). Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 0.5% of the dose within 96 h. The drug was rapidly absorbed and peak plasma radioactivity levels were reached from 1 to 4 h after dosing. Rifabutin was the predominant compound circulating in plasma at the first sampling times, but significant levels of 31-OH rifabutin were detected up to 8-24 h in all species studied. 25-O-deacetyl rifabutin was detected only in rat and man. Polar metabolites were also present, particularly at the later sampling times. The urinary metabolism was studied by radio-HPLC. Rifabutin accounted for 8.5% and 4.6% of the dose in 0-24 h urine of rats and man respectively, whereas in rabbit and monkey urine only traces of this compound were detected. The main known metabolite in all animal species was 31-OH rifabutin; 25-O-deacetyl rifabutin was detected only in rat and man. The remaining urinary radioactivity was mainly due to polar compounds.