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Pharmacokinetics for macrolides? Pharmacokinetics for Aminoglycosides? Pharmacokinetics for  Tetracyclines and Glycopeptide Antibiotics?

Pharmacokinetics for macrolides?

Pharmacokinetics for Aminoglycosides?

Pharmacokinetics for  Tetracyclines and Glycopeptide Antibiotics?

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Pharmacokinetics for macrolides

Macrolides are a class of broad spectrum antibiotics of large molecular size. The class includes erythromycin, clarithromycin, and azithromycin, among others

Pharmacokinetics deals with the action of the drug in the body over a period of time, encompassing issues of absorption, distribution, metabolism, and elimination.

  • The pharmacokinetic properties of macrolide antibiotics differ based on their chemical structure. In low pH environments, such as in the stomach, erythromycin is degraded
  • Macrolides work by binding to a specific subunit of ribosomes in susceptible bacteria, thereby inhibiting the formation of bacterial proteins. In most organisms this action inhibits cell growth; however, in high concentrations it can cause cell death.
  • The 8,9-anhydro-6,9-hemiketal intermediate is inactive as an antibiotic but may cause the gastrointestinal adverse effects that have been associated with erythromycin.
  • This intermediate is then further metabolized into the inactive anhydroerythromycin, erythromycin-6,9;9,12-spiroketal.
  • Clarithromycin is more acid-stable than erythromycin and is not degraded as extensively in the stomach.
  • Azithromycin is even more stable at low pH, resulting in a longer serum half-life and increased concentrations in tissues compared to erythromycin.
  • As a result of their better stability at low pH, azithromycin has an oral bioavailability of 37% and clarithromycin has an oral bioavailability of 55%, compared to an oral bioavailability of 25% for erythromycin.
  • Peak serum concentrations of azithromycin and clarithromycin are lower than for erythromycin of the same dose.
  • Macrolide absorption in the intestine is limited by P-glycoprotein efflux transporters.
  • Macrolides are lipophilic and are widely distributed in blood and tissues. Once in the bloodstream, macrolides preferentially bind alpha-1-acid glycoprotein, the binding protein found in the highest concentration after albumin.
  • Macrolides concentrate in phagocytes, which then transport the drug to the site of infection. Concentrations in phagocytes of clarithromycin and azithromycin are 400 times and 800 times that of what is found in the serum.
  • The macrolides are inactivated in the liver, and the major route of elimination is in the bile. They have low toxicity, and serious untoward effects are rarely encountered.

Pharmacokinetics for Aminoglycosides

Aminoglycosides are neither protein bound nor biotransformed. The major route of elimination is glomerular filtration, and aminoglycosides undergo some tubular reabsorption.

Aminoglycosides are the mainstay in the treatment of serious gram negative infections including catheter-associated infections.

  • They are not metabolized and are rapidly excreted as such by glomerular filtration resulting in a plasma t½ of approximately two hours in those with normal renal function.
  • Inhibition of protein synthesis. Once inside the bacterial cell, aminoglycosides bind to the 30s ribosomal sub-unit and cause a misreading of the genetic code.
  • This subsequently leads to the interruption of normal bacterial protein synthesis.
  • Due to the almost exclusive excretion from the body by glomerular filtration, the elimination rate of aminoglycoside antibiotics is greatly affected by impairment of renal function.
  • In the neonatal period, the absorption rate after intramuscular injection appears to be faster than reported in adults and the volume of distribution is significantly larger.
  • The major pharmacokinetic difference between neonates, infants and adults is the slower elimination: for instance, half-lives which average around 2 hours in adults with normal renal function can reach and sometimes exceed 5 to 6 hours during the very first days of life.

Pharmacokinetics for  Tetracyclines and Glycopeptide Antibiotics

Tetracyclines are a class of broad-spectrum antibiotics used in the management and treatment of a variety of infectious diseases. Naturally occurring drugs in this class are tetracycline, chlortetracycline, oxytetracycline, and demeclocycline.

Glycopeptide antibiotics include the anti-infective antibiotics vancomycin, teicoplanin, telavancin, ramoplanin and decaplanin, corbomycin, complestatin and the antitumor antibiotic bleomycin.

In general the tetracyclines can be divided into three groups based on their pharmacokinetic and antibacterial properties.

Group 1: This group consists of the older agents which have reduced absorption and are less lipophilic than newer drugs in group 2.

  • Examples are tetracycline, oxytetracycline, chlortetracycline, demeclocycline (demethyl chlorotetracycline), lymecycline, methacycline and rolitetracycline. All can be administered orally except for rolitetracycline.
  • Absorption is variable ranging from 0% to almost 90%; however, for most agents it is in the range 25–60%.
  • Serum concentrations rise slowly after oral administration with absorption occurring in the stomach, duodenum and small intestine. Cmax (mg/L) depends on dose, but is generally in the range 1–5 mg/L

Group 2: These drugs are more or less completely absorbed and are 3–5 times more lipophilic than drugs in group 1.

  • This may improve their tissue distribution but convincing data is absent. They are available in oral and intravenous formulations. Examples are doxycycline and minocycline.
  • Doxycycline is said to be almost completely absorbed with a bioavailability of more than 80% with an average of 95%.
  • Absorption takes place in the duodenum.
  • The half-life of absorption is 0.85 ± 0.41 h.
  • The peak concentration (Cmax, mg/L) varies with dose being 15.3 mg/L 4 h after a dose of 500 mg orally

Group 3: This group includes the developmental compounds aminomethylcyclines.

  • These antibiotics are active in vitro against many bacteria with acquired resistance to tetracyclines.
  • There are no data on absorption of tigecycline, but its oral bioavailability is reported to be limited.
  • A light breakfast did not have a significant effect on iv tigecycline pharmacokinetics.
  • The volume of distribution is large with initial values of volume of distribution at steady state (Vss) being >10 L/kg. Total volumes of distribution are 350 L in women and 500 L in men.

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