No abstract

Teicoplanin, a lipoglycopeptide antibiotic, consists of five major components (A2-1 through A2-5), one hydrolysis component (A3-1), and four minor components (RS-1 through RS-4). All the major components contain an N-acyl-1-D-glucosamine, but they differ in the lengths and branchings of their acyl-aliphatic chains.Previous studies with radiolabeled teicoplanin in rats and humans have shown that the drug is eliminated by the renal route and that metabolic transformation is very minor, about 5%. A possible metabolic transformation of teicoplanin into A3-1 was also suggested. In the present study in humans, two metabolites (metabolites 1 and 2; 2 to 3% of total teicoplanin) were isolated after intravenous administration of radiolabeled teicoplanin. After purification, their structures were determined by fast atom bombardment mass spectroscopy and 'H nuclear magnetic resonance spectroscopy on the basis of the well-known correlations established in this field, and they were found to be new teicoplaninlike molecules, bearing 8-hydroxydecanoic and 9-hydroxydecanoic acyl moieties. This metabolic transformation is likely due to hydroxylation in the Q-2 and Q-1 positions for metabolites 1 and 2, respectively, of the C-10 linear side chain of component A2-3. This might explain the low extent of metabolism of teicoplanin if we consider that only component A2-3 has a linear chain that is susceptible to such oxidation.Teicoplanin (9) is a glycopeptide antibiotic that consists of a mixture of five major components designated A2-1, A2-2, A2-3, A2-4, and A2-5 and one more polar component designated A3-1 (5); minor components are also present (4, 8). All teicoplanin components are glycopeptide analogs with molecular weights that range from 1564.3 to 1907.7. The A3-1 component is the core glycopeptide that is common to all teicoplanin components that have been identified; it has a linear heptapeptide aglycone, an a-D-mannose, and an acetyl-o-D-glucosamine. All the components of the A2 group contain an additional N-acyl-p-D-glucosamine and differ only in the nature of this acyl-aliphatic chain (1, 4, 8) (Fig. 1). Teicoplanin components can be separated by gradient reversed-phase high-pressure liquid chromatography (HPLC) (Fig. 2) (13), by which it has been found that the A3-1 component is more polar than the A2 group components.Recovery studies with radiolabeled teicoplanin in rats (2, 16) and humans (7) following intravenous (i.v.) administration showed that the antibiotic is eliminated mainly by the renal route. In rats, approximately 70% of the administered dose is eliminated in 24 h, and 76% is eliminated in 120 h (2). In humans, elimination is slower; approximately 50% of the administered dose is recovered in the urine collected over 0 to 48 h after drug administration and 80% is recovered by 16 days (7). A study in rats with i.v. administration of teicoplanin showed little metabolic transformation of the antibiotic; in urine collected over 0 to 24 h after drug administration, no more than 3 to 5% of the dose eliminated was fo...

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.

The pharmacokinetic profile of [14C]teicoplanin was studied in male Sprague-Dawley rats given a single 10,000-U/kg intravenous dose. The disposition of the antimicrobial activity in the body was estimated by a three-compartment open model. Plasma concentration data were fitted to a three-exponent equation. The profile of total 14C in plasma was similar to that of the microbiological activity. The cumulative recovery of total 14C 5 days after drug administration averaged 76.3% of the administered dose in the urine and 8.7% in the feces. The residual dose remaining in the animal carcasses was 11.1%. Teicoplanin was widely distributed in the body. In almost all organs, the maximum concentration of [14C]teicoplanin was already reached at the first time of killing, which was 0.25 h after the administration of drug. The liver, kidneys, skin, and fat contained most of the residual dose found in the animal carcasses 120 h after administration and behaved as a deep compartment with the adrenal glands and spleen.