Fluoroquinolones distribution

Fluoroquinolones distribute into most tissues with an apparent volume of distribution of 1.5 to 2L/kg. They have serum half-lives of 4 hours and renal clearance of 6mL/rain/kg clearance is reduced in renal failure. They are -40% protein bound and metabolized by hepatic conjugation (UGT) they undergo little phase I metabolism. Symptoms of toxicity include restlessness, diarrhea, and gastrointestinal upset. Skin rash may be a sign of sensitivity to fluoroquinolones. 

S., Couet, W., In vitro and in vivo investigations on fluoroquinolones efFects of the P-glycoprotein efflux transporter on brain distribution of sparfloxadn, Eur. J. Pharm. Sci. 2000, 12, 85-93. 

In terms of pharmacokinetics, LVX has an excellent profile. With an oral dose of 500 mg, LVX has a bioavailability of >99%, an AUC range of 41.9-47.7 mgh/mL, Cmax of 4.5-6.2 mg/mL, a clearance of 10.5-11.9 L/h, and a volume of distribution (Vd) of 1.3 L/kg (Hurst et al., 2002). In terms of protein bound material, only 24-38% is affected (Fish, 2003). Like other fluoroquinolones, there is a 19-44% AUC reduction when co-administered with an aluminum or magnesium antacid or iron sulfate (Qaqish and Polk, 2003). The major metabolite of levofloxacin arises from glucuronidation (Brysk-ier, 2005). 

Mecfianism of Action A fluoroquinolone that inhibits two enzymes, topoisomerase II and IV, in susceptible microorganisms. Therapeutic Effect Interferes with bacterial DNA replication. Prevents or delays resistance emergence. Bactericidal. Pharmacokinetics Well absorbed from the GI tract after PO administration. Protein binding 20%. Widely distributed. Metabolized in liver. Primarily excreted in urine. Half-life 7-14 hr. 

After oral adrninistration, the fluoroquinolones are well absorbed with the bioavailability of 80 to 95 % and distributed widely in body fluids and tissues. Depending upon the newer compound, the different dose regimen have been adopted. The fluoroquinolones are excreted mainly by tubular secretion and by glomerular filtration. 

It has been shown that lipophilic solutes permeate very slowly through membranes of Gram-negative bacteria because of the hydrophilic outer leaflet of the bacterial membranes. The dependence of rate of diffusion and the final equilibrium distribution of lipophilic drugs such as fluoroquinolones and tetracyclines which possess multiple protonation sites has been reviewed [103]. 

Grepafloxacin is a synthetic fluoroquinolone antibiotic with extensive tissue distribution and strong antibacterial activity in vivo (1,2). However, it was withdrawn in 1999 because of its adverse cardiovascular effects, which included dysrhythmias (3-5). 

Suzuki T, Kato Y, Sasabe H, Itose M, Miyamoto G, Sugiyama Y. Mechanism for the tissue distribution of grepafloxacin, a fluoroquinolone antibiotic, in rats. Drug Metab Dispos 2002 30(12) 1393-9. 

The fluoroquinolones are extremely lipid soluble and distribute well. The Vj of enrofloxacin is 2-51/kg in most species. Tissue concentrations greatly exceed plasma concentrations during therapy. Extremely high concentrations are achieved in the kidneys, urine, liver and bile. After mulHple p.o. doses, urine, endometrial tissue and synovial fluid concentrations in horses are higher than serum concentrations. Therapeutic concentrations may be achieved in the CSF. High concentrations occur in milk. The protein binding is low (22%). 

The chemical nature and related physicochemical properties largely govern the distribution and elimination, which refers to biotransformation (metabolism) and excretion, of antimicrobial agents. The majority of antimicrobial agents are weak organic electrolytes, either weak acids (penicillins, cephalosporins, sulphonamides) or weak bases (aminoglycosides, lincosamides, macrolides, diaminopyrimidines, metronidazole), while fluoroquinolones, tetracyclines and rifampin are amphoteric compounds, and chloramphenicol and its... 

ABSORPTION, FATE, AND EXCRETION The quinolones are weU absorbed after oral administration and are widely distributed. Peak serum levels of the fluoroquinolones occur within 1-3 hours of an oral dose of 400 mg. Relatively low serum levels are reached with norfloxacin and limit its usefulness to the treatment of urinary tract infections. Food does not impair oral absorption but may delay the time to peak serum concentrations. Oral doses in adults are 200-400 mg every 12 hours for ofloxacin, 400 mg every 12 hours for norfloxacin and pefloxacin, and 250-750 mg every 12 hours for ciprofloxacin. Bioavailabrlity of the fluoroquinolones exceeds 50% for all agents and 95% for several. The serum half-lives range from 3 to 5 hours for norfloxacin and ciprofloxacin to 20 hours for sparfloxacin. The volume of distribution of quinolones is high, with concentrations in urine, kidney, lung and prostate tissue, stool, bUe, and macrophages and neutrophils higher than serum levels. Quinolone concentrations in CSF, bone, and prostatic fluid are lower than in serum. Pefloxacin and ofloxacin levels in ascites fluid approach serum levels, and ciprofloxacin, ofloxacin, and pefloxacin have been detected in human breast milk. 

The distribution of fluoroquinolones into interstitial fluid has been shown to be predictable from free concentrations in plasma. Like the macrolides group of AMDs, fluoroquinolones achieve high concentrations in leukocytes. Concentrations in lung, liver, and kidney are several times higher than those in plasma. 

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