Pharmacokinetic studies in animals of a new parenteral penem CP-65,207 and its oral prodrug ester.

Gootz, Thomas D.; Girard, Dennis; Schelkley, William; Tensfeldt, Thomas G.; Foulds, George; Kellogg, Michael S.; Stam, John; Campbell, Benedict; Jasys, John; Kelbaugh, P. L.; Volkmann, Robert A.; Hamanaka, E.S.

doi:10.7164/antibiotics.43.422

Cited by 15 publications

(7 citation statements)

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“…The S isomer is absorbed to a greater extent than is the R isomer. Experiments in rats showing that the POM ester of CP-65,207-S is better absorbed when it is given alone than when it is obtained from the mixture (CP-65,207-POM) (7) suggest that the singleisomer prodrug would produce even better absorption in humans than shown in this paper. Oral absorption of other penems has rarely been reported.…”

Section: Resultscontrasting

confidence: 39%

“…Approximately 31% of a parenteral dose of FCE 22101 was excreted as unchanged drug in urine (16). Approximately 65% (17) However, as shown previously in monkeys (7), no intact prodrug is found in peripheral blood, demonstrating that the POM moiety of CP-65,207-POM is hydrolyzed prior to reaching the peripheral circulation. The S isomer is absorbed to a greater extent than is the R isomer.…”

Section: Resultsmentioning

confidence: 59%

“…1). While the isomers have very similar antibacterial activities, in vitro studies and animal experiments indicate that the S isomer is more resistant to hydrolysis by the renal dipetidase enzyme than the R isomer is (7). The pivaloyl-oxymethyl (POM) esters of CP-65,207 (CP-65,207-POM; Fig.…”

mentioning

confidence: 99%

“…The pivaloyl-oxymethyl (POM) esters of CP-65,207 (CP-65,207-POM; Fig. 1) are absorbed in rats and beagle dogs, suggesting that they would be absorbed in humans (7). Here Upon receipt of these samples, they were defrosted, buffered at pH 6.0 with an equal volume of 0.5 M phosphate buffer, and then refrozen at -20°C until assay.…”

mentioning

confidence: 99%

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Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Foulds

Knirsch

Lazar

et al. 1991

Antimicrob Agents Chemother

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CP-65,207 is a new broad-spectrum penem antimicrobial agent that is a 1:1 mixture of two stereoisomers. Five minutes after a 10-min intravenous infusion of 1 g of CP-65,207 to volunteers, mean concentrations in serum were 33 ,ug of the R isomer per ml and 29 tig of the S isomer per ml. Following rapid distribution, half-lives of the isomers were 53 and 55 min, respectively. Concentrations in urine exceeded 800 ,ug of each isomer per ml. Recovery of the S isomer in urine (46%) was much greater than recovery of the R isomer (26%). The serum kinetics of the S isomer (volume of distribution, 319 ml/kg; total clearance, 315 ml/min; elimination rate constant, 0.80 h-1) were similar when it was given alone and when it was contained in 207, demonstrating that the presence of the R isomer has little effect on the serum kinetics of the S isomer. However, when the S isomer was given alone, the urinary recovery of intact S isomer (36%) was substantially lower than that when it was given with the R isomer as 207 (57%). Administration of the S isomer alone did not produce the unpleasant sulfurous odor in urine that was observed following administration of 207. Oral doses of a prodrug, which contained 1 g of CP-65,207, produced peak concentrations in serum of 1.6 ,ug of the R isomer per ml and 1.8 ,ug of the S isomer per ml. Approximately 36% of the S-isomer component was absorbed, and 20% of this isomer was recovered in urine. A 1-g oral dose of the prodrug of the single S isomer provides concentrations in serum above 1.0 ,ig/ml (the MIC for 90% of over 1,000 hospital pathogens) for 3.5 h, suggesting that the drug given orally will prove to be efficacious against many infections.Carbapenem and penem antimicrobial agents are betalactams that usually demonstrate a broad spectrum of activity and a high potency in vitro. However, penems and carbapenems also are susceptible to hydrolysis by the renal dehydrodipeptidase found in the brush border cells of animal and human kidneys (9,11,14). Thus, a renal dipeptidase inhibitor is coadministered with imipenem, the first member of this group of antimicrobial agents to be used commercially (14). Some penems are orally absorbed either as the parent molecule (9, 13) or after incorporation into a prodrug (5,16). Given the potent antibacterial activity of penems and carbapenems, research continues in an effort to find new agents with potential clinical utility (10, 12).CP-65,207 (2) is a potent broad-spectrum antibacterial agent with activity comparable to that of imipenem, with the exception that it has significantly lower activity against Pseudomonas aeruginosa (8). The MIC for 90% of over 1,000 hospital pathogens was approximately 1.0 jig/ml (8).CP-65,207 is a mixture of a more polar R isomer (CP-65,207-R) and a less polar S isomer (CP-65,207-S; also called 429) in approximately a 1:1 ratio (Fig. 1). While the isomers have very similar antibacterial activities, in vitro studies and animal experiments indicate that the S isomer is more resistant to hydrolysis by the renal dipetidase e...

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Section: Resultscontrasting

confidence: 39%

Section: Resultsmentioning

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics of the penem CP-65,207 and its separate stereoisomers in humans

Foulds

Knirsch

Lazar

et al. 1991

Antimicrob Agents Chemother

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“…The in vitro activity of CP-65,207 was previously reported by Gootz et al (3); CP-65,207 is a mixture of stereoisomers of the optically pure CP-70,429. CP-70,429 is a new penem antibiotic, which is stable to renal dehydropeptidase I (2,8). We report here the in vitro antibacterial activity of CP-70,429 and its stability to various types of P-lactamases.…”

mentioning

confidence: 99%