Penicillins plasma protein binding

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

Penicillin Source Acid Resistance Oral Absorption (%) Plasma Protein Binding (%) p-Lactamase Resistance (S. aureus) Spectrum of Activity ainical Use... 

Roughly 80-90% of the salicylate in plasma is bound to proteins, especially albumin, at concentrations encountered clinically the proportion of the total that is bound declines as plasma concentrations increase. Hypoalbuminemia, as may occur in rheumatoid arthritis, is associated with a proportionately higher level of free salicylate in the plasma. Salicylate competes with a variety of compounds for plasma protein binding sites these include thyroxine, triiodothyronine, penicillin, phenytoin, sulfinpyrazone, bilirubin, uric acid, and other NSAIDs such as naproxen. 

PENICILLINS ANTICANCER AND IMMUNOMODULATING DRUGS - METHOTREXATE t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Penicillins 1 renal elimination of methotrexate by renal tubular secretion, which is the main route of elimination of methotrexate. Penicillins compete with methotrexate for renal elimination. Displacement from protein-binding sites may occur and is only a minor contribution to the interaction Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasias, liver toxicity and pulmonary toxicity. Do FBCs and LFTs prior to concurrent treatment... 

Being weak acids with a pfCg of 2.7, penicillins have low values (typically 0.2-0.31/kg). After absorption, penicillins distribute mainly into the ECF. CSF concentrations are 10% of plasma concentrations unless the meninges are inflamed. Penicillins distribute into milk but reach only subtherapeutic concentrations for most bacteria. Penicillins cross the placenta but are not associated with producing adverse effects in the fetus. Protein binding is considered to be moderate (52-54%). 

The penicillins and cephalosporins ((3-lactam antibiotics) are weak organic acids that, due to their low pfCa values, are predominantly ionized in the blood plasma. Binding of (3-lactam antibiotics to plasma proteins (albumin) differs between individual penicillins (from 16-22% for ampicillin to over 80% for cloxacillin and nafcillin) and individual cephalosporins (from 15-20% for cephalexin and cefadroxil to over 80% for cefazolin, cefoperazone and ceftriaxone). The consequence of extensive protein binding on clinical efficacy of (3-lactam antibiotics is incompletely understood, apart from decreasing the availability of the drug (unbound fraction) for extravascular distribution. Because of their high degree of ionization in the plasma and consequently relatively low solubility in lipid, the extravascular distribution of (3-lactam... 

Binding of drugs, including penicillin V, with plasma proteins has been reviewed recently 133, 134 Studies correlating serum protein binding with partition coefficients were summarized in section 5.2. 

Arimori K, Nakano M, Otagiri M, Uekama K. Effects of penicillins on binding of phenytoin to plasma proteins in vitro and in vivo. Biopharm DrugDispos (1984) 5,219-27. 

Albumin is a protein polypeptide. Albumin has a molecular weight of 66.5 kDa and is the most abundant plasma protein, which is present in the concentration of 35-50 g/L in human serum and is synthesized in the liver. Human serum albumin (HSA) has a half-life of 19 days. It acts as a solubilizing agent for long chain fatty acids and is therefore essential for the transport and metabolism of lipids. It binds very well to penicillins, sulfonamides, indole compounds, benzodiazepines, copper, and nickel in a specific and calcium and zinc in a relatively nonspecific manner. It is responsible for osmotic pressure of the blood. 

Serum albumin is the most abundant plasma protein (3.5-5.5%) and is responsible for the binding and transport of various metabolically and pharmacologically active molecules, e.g., bilirubin, uric acid, vitamin C, acetylcholine, cholinesterase, adenosine, aureomycin, barbiturate, Chloromycetin, digitonin, fatty acids, atabrine, neosilversalvarsan, penicillin, salicylate,/ -aminosalicylate, sulfonamide, streptomycin, acid dyes, histamine, triiodothyronine, and thyroxine (Bennhold, 1962 Putnam, 1975). Moreover, albumin tightly binds various metal ions, e.g., Zn (Giroux,... 

Figure 7.10 Bacterial cell wall synthesis. 1) Alanine molecules are added to a carbohydrate tripeptide to form a "T" shaped cell wall precursor. This reaction is inhibited by D-cycloserine. 2) The precursor is transported across the plasma membrane by a carrier. Vancomycin inhibits the transport process. 3) The transporter is recycled to the inside of the cell to carry other precursors. Bacitracin inhibits this step. 4) The precursor is linked to the existing cell wall structure by transpeptidase. Penicillins, cephalosporins, imipenem and aztreonam inhibit the transpeptidase. Transpeptidase is one of several penicillin binding proteins and is not the only site of penicillin action.

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