Distribution of azithromycin into brain tissue, CSF, and eye

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

Distribution of azithromycin into brain tissue, CSF, and eye

Post by Martian » Thu 26 Jul 2007 18:40

Free full text: http://aac.asm.org/cgi/reprint/40/3/825 ... id=8851625

Antimicrob Agents Chemother. 1996 Mar;40(3):825-6.

Distribution of azithromycin into brain tissue, cerebrospinal fluid, and aqueous humor of the eye.

* Jaruratanasirikul S,
* Hortiwakul R,
* Tantisarasart T,
* Phuenpathom N,
* Tussanasunthornwong S.

Department of Medicine, Prince of Songkla University, Hat Yai, Songkla, Thailand.

To measure the concentrations of azithromycin in the central nervous system, 20 patients with brain tumors (group I) received a single 500-mg oral dose of azithromycin either 24, 48, 72, or 96 h prior to the tumor removal operation and 10 patients with cataracts undergoing surgery (group II) and 7 patients scheduled to undergo lumbar puncture (group III) received the same dose of azithromycin 24 h prior to the operation or procedure.

Serum from all patients, brain tissue from group I, aqueous humor from group II, and cerebrospinal fluid from group III were assayed for azithromycin concentration. The mean concentrations of azithromycin in brain tissue 24, 48, 72, and 96 h after administration were 2.63 ± 2.58, 3.64 ± 3.81, 0.74 ± 0.37, and 0.41 micrograms/g, respectively. In contrast, the concentrations of azithromycin in cerebrospinal fluid and aqueous humor of the eye were very low or undetectable.

Therefore, these data show that azithromycin appears to be widely distributed into brain tissue but not into cerebrospinal fluid or aqueous humor of the eye.

PMID: 8851625 [PubMed - indexed for MEDLINE]

Joe Ham
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Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Re: Distribution of azithromycin into brain tissue, CSF, and eye

Post by Joe Ham » Fri 27 Jul 2007 7:38

I don't think this study shows what it tries to prove, that Zith passes the BBB well.
It doesn't prove that because the subjects had brain tumors so there was a high probability that the BBB was already compromised.

The same method was used to show that Rulid (roxithromycin) was the only macrolide with good BBB penetration. All the test subjects were scheduled for brain surgery before they were started on Zith. Why would they need brain surgery unless there was something wrong with the brain?
It's not done for fun ya know.

However, Zith has some interesting properties and because it has a lower molecular weight than Rulid and some lipid solubility it may do quite well in the brain.
It has a long half-life, about 3 days, and very good intracellular activity and persistence, long wash out time of about 2 weeks, called post-antibiotic-effect by ducs. For that reason it can build up to toxic levels so some LLMDs recommend reducing dosage to 125 mg QOD after about a week.

Here is some data on Zith that I gathered in '05. Maybe it's time for me to update this file.

**********************************************

HIGHLITES Long half-life and very good intracellular penetration and accumulation. Data from Pfizer except where noted otherwise.

TRADE NAMES Zithro, Zithromax

FAMILY Macrolide

FORM Pill (suspension for pediatrics)

MODE OF ACTION b'static, inhibits protein synthesis by binding to 50s ribosomal subunit

ABSORPTION small intestine

BIOAVAILABILITY 38%

TISSUE PENETRATION Accumulation in liver, spleen, heart, brain were 10 to 200 times greater than serum in mice treated for 10 days (1991):
http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

MOLECULAR WEIGHT 785 (lipid solubility promotes tissue penetration and
concentration in the brain)

METABOLISM P450 enzymes

ELIMINATION mostly via liver

SERUM PEAK 3.2 hr

HALF LIFE 68 hours, in leukocytes 34 to 57 hrs

DOSAGE Day 1, 500 mg, then 250 mg qd for a week, the 125 qod

MIC / MBC

INDICATIONS Otitis media, sinusitis, mycobacteria, helicobacter, staph, toxoplasmosis gondi, haemophilus influenza.

CONTRAINDICATIONS other macrolide allergy

DRUG INTERACTIONS ergotamine, dihydroergotamine, digoxin, cyclosporin,
terfenadine, astemizole, zidovudine, reduces rifampin
concentration 15%

HERB INTERACTIONS caffein

FOOD INTERACTIONS take one hour before or two hours after meal,
impedes absorption by 24%, avoid Al, Mg near dose time.
"Can be taken with or without food" (Pfizer)

SIDE EFFECTS 95% none, 5% diarrhea, nausea, gut cramps, vomiting

ALLERGIC REACTION oral thrush - white, furry, sore tongue and mouth
• vaginal thrush - sore and itchy vagina and/or white discharge
• nausea (feeling sick), loss of appetite, vomiting, stomach pain, indigestion, wind, constipation, loose bowel motions
• unusual weight gain or swelling of the arms or legs
• palpitations (fast or irregular heart beat), chest pain
• dizziness, headache, spinning sensation
• tiredness, drowsiness
• muscle or joint aches
• hearing loss or ringing in the ears.

SERIOUS ALLERGIC REACTIONS;
diarrhoea (loose bowel motions)
• symptoms of sunburn such as redness, itching, swelling or blistering which may occur more quickly than normal
• asthma, wheezing or shortness of breath
• swelling of the face, lips or tongue which may lead to difficulty swallowing or breathing
• hives, itching or skin rash
• fainting
• yellowing of the eyes or skin, also called jaundice
• bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
• signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
• blood in the urine or bowel motions
• severe blistering or peeling of the skin
• convulsions (fits).

"These symptoms are usually rare but may be serious and need urgent medical attention." (Pfizer)

IMMUNE SUPPRESSION Yes 2004: http://www.ncbi.nlm.nih.gov/entrez/quer ... s=15499531

COST

MORE DETAILS
Lab values may increase for;
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Creatine kinase and
Gamma-glutamyltransferase and
Lactate dehydrogenase
(serum values may be increased)
Bilirubin, serum and
Potassium, serum
QT re-polarization time may be increased

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

Re: Distribution of azithromycin into brain tissue, CSF, and eye

Post by Martian » Fri 27 Jul 2007 14:31

Joe Ham wrote:I don't think this study shows what it tries to prove, that Zith passes the BBB well.
It doesn't prove that because the subjects had brain tumors so there was a high probability that the BBB was already compromised.
You do have a point that the BBB of (some of) these subjects may have been compromised, but I am not convinced that it's a high probability. I guess one can have a brain tumor with intact BBB. Anyway, I do not know of a study that has confirmed this study.
Joe Ham wrote:BIOAVAILABILITY 38%
Are you sure it's that low, even when taken on empty stomach?
Joe Ham wrote:HERB INTERACTIONS caffein
Interesting. Do you know what kind of interaction? Does it count for other macrolides too?
Joe Ham wrote:FOOD INTERACTIONS take one hour before or two hours after meal,
impedes absorption by 24%, avoid Al, Mg near dose time.
"Can be taken with or without food" (Pfizer)
I believe it is advised to take azithromycin without food if you can tolerate that. In contrary, clarithromycin is thought to be better absorbed when taken WITH some food.
Joe Ham wrote:ALLERGIC REACTION
SERIOUS ALLERGIC REACTIONS
I don't think you can call all of that allergic reactions. I think some are side effects without being an allergic reaction.
Nevertheless: it's useful to collect data about antibiotics and put them in one post/topic.

Joe Ham
Posts: 489
Joined: Fri 27 Jul 2007 6:15
Location: New Mexico, USA

Re: Distribution of azithromycin into brain tissue, CSF, and eye

Post by Joe Ham » Sat 4 Aug 2007 20:30

The bioavailability of Zith at 38% sounds reasonable to me. I think the number came from the Pfizer AU site and is when taken without food. Taken with food reduces that by 24%. Pfizer does not consider that to be significant. Some other antibiotics have numbers in the 20s, some drugs even lower. Morphine is 15% and dirithromycin (Dynabac), a prodrug, about 10%.
http://en.wikipedia.org/wiki/Dirithromycin

Then there is the issue of how bioavailability is measured. If it is by serum level only then there is more to the story because Zith and some other drugs have good intracellular penetration and accumulation (as noted above) and so serum levels don't tell the whole story of how effective the drug is against intracellular pathogens.

It seems that Zith is slow to get into tissue but once it is in there it is even slower to get out, a dynamic that is accounted for and recognized as a long post-antibiotic effect, PAE.

After thinking about the study by Jaruratanasirikul, et al, it seemed flawed because the possibility of compromised BBB was not mentioned. Potentially confounding factors are usually avoided by the study design. I find the last comment in the abstract to be revealing:

"Therefore, these data show that azithromycin appears to be widely distributed into brain tissue but not into cerebrospinal fluid or aqueous humor of the eye."

Maybe there is an explanation in the full version which I will read later today.
********************************

"Herb interactions: caffeine"

I read that in an early paper that assumed Zith was metabolized by the the same P450 enzymes as the other macrolides; it is NOT.
Good that you caught the error, thanks.

An interesting paper on the cytochrome system is,

http://www.pswi.org/professional/pharma ... chrome.pdf

The distinction between side effects vs allergic reactions is something we could discuss all day without coming to a clear conclusion because there is so much overlap.
However we can rule out herx reactions, even though the symptoms may be somewhat similar, because Zith and the other macrolides are b'static. (Just thought I'd throw that out to stir the pot.)

jjazzini
Posts: 1
Joined: Sat 8 May 2010 21:50

Re: Distribution of azithromycin into brain tissue, CSF, and

Post by jjazzini » Sat 8 May 2010 21:59

HI there,

I know this is not completly related to the forum though I'm in need of desperate HELP!
I have taked 1000mg of Azithromycin about 7 weeks ago for a suspected STD (whch came back negative) and am still suffering Anxiety, Insomia and Tinnutis.

After seeing a number of doctors who can not relate the side effect to the drug, I am sure it is for that there are forms on the web with patients who have suffered the same.

What I would like to know, I have taken Zithromax (Azithromycin) in the past quite a few times over approximently 7 years to 8 years, is it possible once the drug enters the body it stays in your tissues or fuild and evertime you add more it bulds up until it is at toxic levels hence my serous side effect, Im no medical person though this drug has effected me so much I have been reading nearly everything related to it.

Any help would be apprieciated....

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