Statins distribution

Most statins are highly plasma protein hound and highly lipophilic. The exceptions are pravastatin and rosuvastatin, but it is not known whether they distribute into ascitic fluid [19, 21]. The statins, except possibly rosuvastatin and fluvastatin, are substrates for P-glycoprotein, a pump which is responsible for the excretion of drugs back into the gut, from where they may be reabsorbed or excreted in the faeces [23, 24]. 

The distribution of a compound in the human body can also be partially related to the absorption properties. There are specific transport systems that are expressed in certain tissues that can influence the distribution of the compound. For example, rosuvastatin, a new member of the statin family is transported by the OATP-C carrier system, which is selectively expressed in the liver, making this compound selectively distributed into this organ [27]. In general it is not possible to derive computational models for these selective transport systems since there is not yet enough experimental information and data to support the model building and validation. Nevertheless, there are three properties that are commonly used to describe the distribution of a compound in the human body the solubility, the unspecific binding of the compound to plasma proteins and the volume of distribution. 

In 696 patients taking atorvastatin and 235 taking lova-statin for 1 year there were no significant differences in the distribution of lenticular opacities or cortical opacities and spokes between the two drugs (4). 

Myalgias related to statin use are quite common, occurring in up to 10 % of patients exposed [19]. Clinicians often measure circulating levels of nonspecific markers of myocyte damage (e.g., CK) to estimate severity. Myalgias accompanied by a mild elevation in serum CK level occur in approximately 1 % of patients exposed [20, 21], Myopathy (CK >10-fold upper limit of normal) is less common, 0.1 %, and rhabdomyolysis (CK >50-fold upper limit of normal) is extremely rare [14, 15]. Graham and colleagues surveyed more than 250,000 statin-exposed patients, and reported rhabdomyolysis rates of 0.000044 events per person-year [18]. Similar rates have been observed for more than 100,000 first-time statin users followed in the UK over a course of 20 months [22], Event rates increase when statins are used in the presence of other medications known to alter their absorption, distribution, metabolism, and elimination (ADME) [23, 24], Event rates also increase with comorbidity (e.g., thyroid disease) [21, 25]. 

The clinical severity of statin-induced muscle toxicity is clearly influenced by variability in enzymes modulating statin disposition (absorption, distribution, metabolism, and elimination, ADME) (Fig. 1) [40], While many statins undergo phase I oxidation (atorvastatin, fluvastatin, lovastatin, simvastatin), the impact of phase I oxidation on others (pitavastatin, pravastatin, rosuvastatin) is very limited [41],... 

Westwood, R., A. Bigley, K. Randall, A. Marsden, and R. Scott. 2005. Statin-induced muscle necrosis in the rat Distribution, development, and fiber selectivity. Toxicologic Pathology 33 246-257. 

Transporters also contribute to the drug distribution in certain tissues. Most statins are taken up into the hepatocytes by OATP, excreted into the bile by efflux transporters, and reabsorbed in the intestine, thereby effectively undergoing enterohepatic circulation and maintaining high concentrations in... 

Distribution Skeletal muscle Outcome Necrosis Sequela Myalgia, myopathy, and rhabdomyolysis due to statins... 

Fig. 7. Synthesis of the statine library B. Reagents anti conditions (a) TentaGel S-NH2 resin (0.3 mmol/g) distributed into seven reaction vessels (b) 3 Eq each Boc-Lys(Boc)-OH, HOBt, 5 Eq DIG, DCM (c) encode using three tags (d) 50% TFA/ DCM, 1 h (e) 5 Eq each 4-bromomethyl-3-nitrobenzoic acid, HOBt, 8 Eq DIG, DGM, 3 h (f) one of seven amines (Fig. 4) 10 Eq amine, THF, 8 h (g) pool and split into three reaction vessels (h) one of three Rg Boc-protected statines (Fig. 4) 4 Eq each statine, HATU, 8 Eq DIEA, DMF, 3 h (i) encoded using two tags (j) pool and split into 31 reaction vessels and encode using 5 tags (k) 50% TFA/DGM, 1 h (1) one of 31 Rc Fmoc-protected amino acids (Fig. 4) 4 Eq each amino acid, HATU, 8 Eq DIEA, DMF, 6 h (m) pool (n) 30% piperidine/DMF, 1 h (o) split into 20 reaction vessels (p) one of 20 Rj) acylation agents (Fig. 4) 4 Eq each of RDGO2H, HATU, 8 Eq DIEA, 6 h (q) hv (365 nm), MeOH, 50 G, 2.5 h.

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