Clarithromycin in vitro activity enhanced by its metabolite

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Martian
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Location: Friesland, the Netherlands

Clarithromycin in vitro activity enhanced by its metabolite

Post by Martian » Thu 6 Sep 2007 4:15

Diagn Microbiol Infect Dis. 1992 Mar-Apr;15(3):259-66.

Clarithromycin in vitro activity enhanced by its major metabolite, 14-hydroxyclarithromycin.

Hoover WW, Barrett MS, Jones RN.

Department of Pathology, University of Iowa College of Medicine, Iowa City.

14-Hydroxyclarithromycin, an active metabolite of clarithromycin, was compared for antimicrobial activity alone and in combination with the parent compound. The 14-hydroxyclarithromycin potency was comparable to that of clarithromycin, but was more active against Haemophilus influenzae (MIC50, 1 microgram/ml). Combination MICs at pharmacokinetic ratios produced end points equal to the most active component of the combination. However, checkerboard MICs and kill-curve studies suggested enhanced interactive effects. Partial synergy and additive interactions were demonstrated in 96% of strains tested with synergy (partial) most often observed among the Enterococcus faecalis, H. influenzae, and staphylococci. To determine the best in vitro test methods for predicting the value of 14-hydroxyclarithromycin, combination disks or ratio MIC tests may not be practical. A modification of the proposed clarithromycin-susceptible breakpoint (less than or equal to 2 micrograms/ml) upward to less than or equal to 4 micrograms/ml (greater than or equal to 14 mm) was suggested to recognize the additional activity contributed by the 14-hydroxy metabolite. This modification should be applied, limited to susceptibility tests of H. influenzae and possibly the enterococci.

PMID: 1533827 [PubMed - indexed for MEDLINE]

Martian
Posts: 1944
Joined: Thu 26 Jul 2007 18:29
Location: Friesland, the Netherlands

Re: Clarithromycin in vitro activity enhanced by its metabolite

Post by Martian » Thu 6 Sep 2007 4:52

An interesting find in the studie below is that 14-hydroxy-clarithromycin was less negatively effected by a lower pH than other macrolides.

J Antimicrob Chemother. 1994 Dec;34(6):1025-9.

Additive effect of clarithromycin combined with 14-hydroxy clarithromycin, erythromycin, amoxycillin, metronidazole or omeprazole against Helicobacter pylori.

Cederbrant G, Kahlmeter G, Schalén C, Kamme C.

Department of Clinical Microbiology, Central Hospital, Växjö, Sweden.

The in-vitro activities of clarithromycin, 14-OH clarithromycin, erythromycin, amoxycillin, metronidazole and omeprazole against Helicobacter pylori were determined at pH 7.2 and 5.5. At pH 5.5 the activities of clarithromycin and erythromycin decreased approximately 16 times while 14-OH clarithromycin was less influenced. Chequerboard titration indicated that the combined activity of clarithromycin and the other compounds was additive.

PMID: 7730216 [PubMed - indexed for MEDLINE]

Martian
Posts: 1944
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Re: Clarithromycin in vitro activity enhanced by its metabolite

Post by Martian » Thu 6 Sep 2007 5:00

while reading about the BBB, and knowing that the macrolides have a bit too high molecular mass for passing the BBB, I had a moment of lucidity. It occurred to me that the metabolite of clarithromycin may have a lower molecular mass! Perhaps low enough to make it pass the BBB easily, but I don't know and I couldn't find it.

So, who knows the molecular mass of 14-hydroxy-clarithromycin?

You can also find several studies saying that the metabolite of clarithromycin has greater activity than clarithromycin against different bacteria. So, I wonder if the antimicrobial activity of 14-hydroxy-clarithromycin is taken into account every time clarithromycin is studied.

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Yvonne
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Re: Clarithromycin in vitro activity enhanced by its metabolite

Post by Yvonne » Thu 6 Sep 2007 12:12

Martian wrote:
So, who knows the molecular mass of 14-hydroxy-clarithromycin?
Urine pharmacokinetic parameters were determined for clarithromycin and > 14-(/R/)-hydroxyclarithromycin only. Renal clearance (CL_R ) was > calculated as Ae_ss /AUC_ss , where Ae_ss is the amount of drug excreted > in the urine over the dosing interval. The percentages of clarithromycin > and its metabolite eliminated in the urine were calculated based on > clarithromycin weight equivalents. The molecular sizes of clarithromycin > and 14-(/R/)-hydroxyclarithromycin were 747.96 and 763.96 Da, respectively.

http://www.pubmedcentral.nih.gov/articl ... rtid=89801
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