Protein inhibitor, plasma

Ibuprofen is the most thoroughly researched 2-ary lpropionic acid. It is a relatively weak, non-selective inhibitor of COX. In epidemiological studies, ibuprofen compared to all other conventional NSAIDs, has the lowest relative risk of causing severe gastrointestinal side effects. Because of this, ibuprofen is the most frequently used OTC ( over the counter , sale available without prescription) analgesic. Ibuprofen is highly bound to plasma proteins and has a relatively short elimination half-life ( 2 h). It is mainly glucuronidated to inactive metabolites that are eliminated via the kidney. 

Cl-Inh belongs to a superfamily of serine protease inhibitors (serpins) and is a major inhibitor of F-XIIa and kallikrein. It is also an inhibitor of activated complement factors C1 q, C1 r, and C1 s. C1 -Inh thus regulates the activation of two important plasma cascade systems. Proteases induce a conformational change in the plasma protein a2-M, which results in entrapment of the protease into the a2-M cage (B4). In vivo, a2-M acts as a second inhibitor of kallikrein. 

L-dopa is not bound to plasma proteins, and the elimination half-life is about 1 hour. The addition ofcarbidopa can extend the half-life to 1.5 hours, and the addition of a COMT inhibitor (e.g., entacapone) can extend it to about 2 to 2.5 hours. 

A similar strategy was employed to identify a DPP-IV inhibitor (6) with good in vivo potency in a mouse model of diabetes [44], Plasma protein binding, as assessed by shift assay (50% serum), was presented for all final compounds. The compound selected as having the best overall profile was active in vivo at 0.1 mg/kg. The activity at 1 h post-dose was consistent with the free drug principle - total plasma concentration 269 nM murine-free fraction 4% unbound plasma concentration 11 nM in vitro potency versus murine DPP-IV 6nM. 

A paper detailing the properties of the multikinase inhibitor ABT-869 (7) did not indicate whether plasma protein binding data were used in the optimization leading to this highly protein-bound (mouse 98.2%, human 99.0%) compound [45]. A dose which provided a 69% reduction in tumor growth and >50% inhibition of receptor phosphorylation and pharmacodynamic response afforded plasma concentration that remained above the cellular IC50 for receptor phosphorylation in the presence of plasma for 4 of 12 h in the bid dosing cycle. 

A study of the potency of the antibiotic daptomycin cited plasma protein binding of 92%, but it claimed only a 2-fold shift in potency in serum (expected 12-fold) [68]. This type of discrepancy is relatively common and can often reflect substantial binding to components in the "serum-free" media. In the cases of HIV-directed non-nucleotide reverse transcriptase inhibitors, this has been dealt with by measuring the unbound drug concentration in the "serum-free" medium and using that data to calculate the intrinsic, serum-free potency [69]. 

A compound that reduces the activity of an enzyme is known as an inhibitor. Inhibitors are usually small molecules but some are peptides or proteins. For example, there are a number of proteolytic enzymes in the blood that have serine in their active site. If the activities of these enzymes are too high, they can cause problems. Consequently, inhibitor proteins, known as serine proteinase inhibitors (serpins), are present in blood indeed, about 10% of all the plasma proteins are serpins (Box 3.4). 

Zidovudine was the first drug of the class. It is a dideoxythymidine analog. It has to be phos-phorylated to the active triphosphate. This triphosphate is a competitive inhibitor of HIV reverse transcriptase. By incorporation into viral DNA it also acts as a chain-terminator of DNA synthesis. Mutations in viral reverse transcriptase are responsible for rapidly occurring resistance. Zidovudine slows disease progression and the occurrence of complications in AIDS patients. It is readily absorbed. However, first pass metabolism reduces its oral bioavailability with some 40%. It readily crosses the blood-brain barrier. Plasma protein binding is about 30%. Zidovudine is glucuronidated in the liver to an inactive metabolite. Its elimination half-life is 1 hour. 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

Duloxetine is a moderate inhibitor of the CYP 2D6 enzyme and may increase the levels of other medications that use this enzyme (Table 1-1). Because of the risk of serotonin syndrome, duloxetine should not be combined with MAOIs. Because duloxetine is highly bound to plasma protein, combination with another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. 

Synergism - a potentiation or prolongation which results in much greater than expected effects. This could involve competitive substrates for an enzyme or receptor, decreased excretion, displaced plasma protein binding, etc. The analgesic propoxyphene (Darvon ) slows down the excretion of ethanol and so increases the depressant effects of the alcohol. Recall the example given earlier of the monoamine oxidase inhibitors used as antidepressants and the tyramine-containing foods which could precipitate a hypertensive crisis. 

Cefoperazone is widely distributed in body tissues and fluids. It is bound to plasma proteins in the circulation. It is excreted primarily in the bile, and is also excreted in urine and poorly in breast milk. Cefoperazone is susceptible to the action of some -lactamases, and thus may be given with a -lactamase inhibitor. 

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