Protease inhibitors with statins

Healthy volunteers were given protease inhibitors and statins, and the authors concluded that simvastatin should be avoided and that atorvastatin could be used with caution in people taking ritonavir and saquinavir (111). Dosage adjustment of pravastatin may be necessary with co-administration of ritonavir and saquinavir. Pravastatin does not alter the pharmacokinetics of nelfinavir, and thus appears to be safe for co-administration. 

Some inducers of CYP3A4 are also inducers of P-glycoprofein These include dexamethasone, rifampin and St. John s wort. The last two have been implicated in the induction of the metabolism of cyclosporin, certain HMG-CoA reductase inhibitors (statins) and several HIV protease inhibitors, with resulting loss of efficacy of these compounds. 

A third dataset was built in order to demonstrate that the descriptor is relevant for estimating binding affinity in a QSAR analysis. This last dataset contains 49 HIV-1 protease inhibitors, the 3D coordinates of which were those used by Pastor et al. (30). It has the four transition-state isosteres—hydroxy ethylene, hydroxyethylamine, statine, and a symmetrical diol. The X-ray structures of molecules numbered 1 and 3-34 have been reported (31), whereas molecules numbered 35-50 were modeled on the crystallographic structure of the complex of HIV-1 protease with L-689,502 solved at 2.25 A resolution (32). The binding affinity is expressed as pIC50 values. 

These aspartic protease inhibitors are also "lead compounds" in the development of inhibitors of HIV protease. As in statine-based inhibitors, the site of occupancy by the catalytic H20 (green in Eq. 12-23) is occupied in the inhibitor by something that mimics a tetrahedral intermediate with - CHOH -P02H etc.bb Tremendous efforts are being expended in designing these inhibitors and considerable... 

The intense interest in y - am i n o - (i -hydroxy acid related peptides has led to a great deal of effort devoted to their synthesis. Statine analogues Ahppa (11), Achpa (12), and Dahoa (13) (Scheme 2), which correspond to the replacement of the chain equivalent of leucine in statine by those of phenylalanine, cyclohexylalanine, and lysine, respectively, were used to synthesize inhibitors of pepsin, renin, and penicillinopepsinJ1314] With the objective of developing highly specific inhibitors, C2-substituted analogues have also been introduced into short, substrate-derived inhibitors, e.g. the a,a-difluoro statine 14 in renin inhibitors,1151 and N -substituted statine derivatives like 15 in HIV-1 protease inhibitors.[16]... 

The naturally occurring inhibitor pepstatin (structure 16.34) binds very tightly to carboxyl proteases Kt with porcine pepsin is 4.5 X 10-11 M.175 The statine residue has a tetrahedral carbon replacing the normal carboxyl carbon, and so... 

According to Rich, new protease inhibitors were produced by replacing statine in pepstatin derivatives with (3S,4S)-4,8-diamino-3-hydroxyoctanecarboxylic acid (DAHOA) 85 a 189a) or 4-amino-3-hydroxy-5-phenylpentanecarboxylic acid (AHPPA) 85b 189b-c>. 

Statins are well absorbed after administration orally, and are metabolised in the liver. They are well tolerated, the commonest adverse effect being transient, and usually minor abnormality of liver function tests in some 1% of patients. Asymptomatic elevation of muscle enzymes (creatine phos-phokinase, CPK) and myositis (with a generalised muscle discomfort) occur more rarely, but is more frequent when statins are combined with other anti-hyperlidaemic drugs such as fibrates and nicotinic acid patients should be counseled about myositis when these drugs are co-administered. Myositis is also more likely with co-administered anti-HIV protease inhibitors, and with drugs that interfere with metabolism of some statins, e.g. ciclosporin. 

Since HMG CoA reductase inhibitors (statins) are partially or completely metabolized by CYP3A4, drug interactions with protease inhibitors can be expected. When nelfinavir was combined with atorvastatin and simvastatin, their AUCs increased by 74 and 505% respectively (17). As myopathy and rhabdomyolysis are concentration-related, simvastatin is contraindicated with any protease inhibitor, not just nelfinavir. Based on the data, the starting dose of atorvastatin should be reduced by about 50%. 

In order to reduce the risk of myopathy the CSM in the UK have advised that statins should be used with care in patients who are at increased risk of this adverse effect. Among other risk factors, they mention concomitant use with fibrates, such as gemfibrozil , (p.llOO), and with inhibitors of CYP3A4 such as ciclosporin , (p.l097), macrolides ,(p.ll04), azoles , (p.l093), and protease inhibitors , (p.1108). They also recommend that patients should be made aware of the risks of myopathy and rhabdomyolysis, and asked to promptly report muscle pain, tenderness, or weakness, especially if accompanied by malaise, fever, or dark urine. A 2002 advisory on the use of statins gives some important safety recommendations, which are useful in the context of interactions ... 

P-Hydroxy-amino acids (Figure 10.7) are multifunctional compoimds with valuable interest as intermediates for the synthesis of statine derivatives (106) [166-168], protease inhibitors [169], antivirals [170, 171], peptide mimetics [172], idulonic acid mimetics, for example, 3R,5R-dihydroxy-L-homoproline (111) [173], immimosup-pressive lipid mycestericin d (112) [174], 3,4-dihydroxyprolines (113) [175], (2S,3R)-2-amino-3-hydroxybutyrolactone, precursor of monobactam antibiotics [176], or L-ffereo-3-[4-(me ylthio)phenylserine] precursor of thiamphenicol (114), florfenicol (115) [177], sialyl Lewis x mimetics (117) [178], p-hydroxyomithine (109), a relevant building block for the p-lactamase inhibitor, clavulanic acid, and the antibiotic and anticancer acivicin [179], surveyed in previous reviews [41,57]. 

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