A series of in vivo, ex vivo and in vitro studies were conducted to determine the pharmacokinetic and pharmacodynamic properties of cefovecin, a new injectable cephalosporin, in dogs. Absolute bioavailability was determined in a two-phase cross-over study in dogs receiving 8 mg/kg bodyweight (b.w.) of cefovecin by either subcutaneous (s.c.) or intravenous (i.v.) route. After s.c. administration, cefovecin was fully bioavailable (100%), the mean maximum plasma concentration (Cmax) was 121 microg/mL and the mean apparent elimination half-life (t1/2) was 133 h. Clearance was measured to be 0.76 mL/h/kg after i.v. dosing. The concentration of cefovecin in urine measured 14 days after s.c. administration was 2.9 microg/mL. Plasma protein binding was determined by equilibrium dialysis; over concentrations ranging from 10 to 100 microg/mL (i.e. up to the approximate Cmax following an 8 mg/kg dose), protein binding of 98.7% to 96.0% was observed, however, binding was lower at higher concentrations. Total and free concentrations of cefovecin were determined in plasma, transudate and exudate collected from dogs previously implanted subcutaneously with tissue cages. Mean peak concentrations of free cefovecin were almost three times higher in transudate than in plasma and remained above 0.25 microg/mL for 19 days. The ex vivo antibacterial killing activity (vs. Staphylococcus intermedius, MIC 0.25 microg/mL) was measured in serum, transudate and exudate collected from dogs which had received 8 mg/kg b.w. of cefovecin subcutaneously. Transudate exhibited higher antimicrobial killing activity than serum. Activity in serum and exudate exhibited a mean reduction in bacterial counts of S. intermedius of at least three log units up to 72 h postadministration. Bactericidal activity (>3 log10 reduction of bacterial counts) was observed in transudate up to 12 days postadministration. The slow elimination and long lasting ex vivo antibacterial killing activity following administration of cefovecin are desirable pharmacokinetic and pharmacodynamic attributes for an antimicrobial drug with 14-day dosing intervals.

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series of in vivo, ex vivo and in vitro studies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross-over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determined in vitro in feline plasma and ex vivo in transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141+/-12 microg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half-life was 166+/-18 h. After i.v. administration, volume of distribution was 0.09+/-0.01 L/kg and mean plasma clearance was 0.35+/-0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21-day postdose period via urinary excretion and up to approximately 25% in faeces. In vitro and ex vivo plasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10-100 microg/mL. Ex vivo protein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 microg/mL (MIC90 of Pasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long-lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14-day dosing interval.

Four novel metabolites of a Penicillium strain, IMI 332995, which has previously been reported to produce paraherquamide and a number of related metabolites, are herein describedm. VM55596 is the first TV-oxide to be found in this family of compounds. Unusiial oxidative substitution is also seen in VM55597. VM55599appears to be the first documented example of the hexacyclic indole species that have long been postulated as biosynthetic precursors of metabolites of the brevianamide, paraherquamide and marcfortine families. 1355 Since the discovery of the potent anthelmintic activity of paraherquamide much interest has been focused on this class of oxindole alkaloids which includes the marcfortines and brevianamides. All are products of Penicillium species and a commonmetabolic pathway has been proposed1}. A number of related metabolites have now been isolated by ourselves2) and others3'40. All previously reported paraherquamide metabolites show variation in substitution at C(14) and N(l l) in addition to the two variants of the ring system fused to the 6 and 7 positions of the indole. The marcfortine family also show analogous substitutions.Wenow describe four further metabolites from our paraherquamide-producing strain including two which, unusually, show additional oxidative substitution at N(12) or C(16) and another which is analogous to the proposed precursor of this class of natural productsX).Taxonomic Studies The morphology of the producing strain has been described2). This strain has now been deposited in the CABInternational Mycological Institute at Kew,UK, under the accession number IMI 332995.IMI 332995 has been compared (Table 1) with a number of Penicillium species obtained from the IMI at Kew. P. paraherquei (IMI 68820) is a known producer of paraherquamide, P. fellutanum (IMI 40232) was included since Ondeyka et al.3) typed their paraherquamide producing culture as P. charlesii which is included under the species P. fellutanum5). Early results on IMI 332995 indicated that certain characteristics were most similar to P. citrinum. Thus the culture P. citrinum IMI 24307 was also examined for comparison.IMI 332995 differs from P. paraherquei in that growth is much slower at 25°C on malt extract and Czapek-yeast extract agars and was also slower on all of the agars tested at 37°C. IMI 332995 differs from P.fellutanum in that the penicillus is biverticillate as opposed to monoverticillate and growth was slower on n Present address: SmithKline BeechamPharmaceuticals Chemotherapeutic Research Centre, Brockham Park, Betchworth, Surrey RH3 7AJ, England. m Metabolites 1, 2 and 3 are subjects of International Patent Application WO91/09961.

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