Rosuvastatin 5 S-lactone forms in the human body through specific metabolic pathways.
the verdict
INSUFFICIENT LEANING
refutedsupported
the weight of evidence
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Published literature confirms the presence and quantification of rosuvastatin-5 S-lactone in human plasma and acknowledges the general interconversion and glucuronidation pathways of statins, but lacks detailed, specific evidence regarding the exact metabolic pathways forming rosuvastatin-5 S-lactone in the human body.
The drug-drug interaction profile of atorvastatin confirms that disposition is determined by cytochrome P450 (CYP) 3A4 and organic anion transporting polypeptides (OATPs). Drugs that affect gastric emptying, including dulaglutide, also affect atorvastatin pharmacokinetics (PK). Atorvastatin is a carboxylic acid that exists in equilibrium with a lactone form in vivo. The purpose of this work was to assess gastric acid-mediated lactone equilibration of atorvastatin and incorporate this into a physiologically-based PK (PBPK) model to describe atorvastatin acid, lactone, and their major metabolites. In vitro acid-to-lactone conversion was assessed in simulated gastric fluid and included in the model. The PBPK model was verified with in vivo data including CYP3A4 and OATP inhibition studies. Altering the gastric acid-lactone equilibrium reproduced the change in atorvastatin PK observed with dulaglutide. The model emphasizes the need to include gastric acid-lactone conversion and all major atorvastatin-related species for the prediction of atorvastatin PK.
1 , 2 Following the administration of atorvastatin, inactive lactone metabolites are also present in plasma, as atorvastatin lactone and the
3 , 4 , 5 , 6 In addition, there is clear in vitro and in vivo evidence of the role of organic anion transporting polypeptides (OATPs) in the disposition of the acid forms; both coadministration of OATP inhibitors as well as polymorphisms in the solute carrier organic anion transporter family member 1B1 gene ( SLCO1B1 ) significantly increase plasma exposure. 1 , 7 , 8 Conversely, although atorvastatin lactone exists at an approximately 1:1 ratio with atorvastatin acid in plasma, mechanisms regarding its formation in vivo are not well understood.
In vitro , atorvastatin lactone can be formed via hepatic uridine diphosphate glucuronosyltransferase (UGT)–mediated metabolism of atorvastatin acid. 9 However, the role of this pathway in vivo has not been clearly defined given the lack of selective, potent inhibitors of UGTs and that genetic variants reveal minimal and inconsistent effects on the pharmacokinetics (PK) of both atorvastatin acid and lactone. 10 , 11 On the other hand, it has been demonstrated in vitro that atorvastatin acid and lactone can interconvert nonenzymatically. Kearney et al .
12 reported that, in buffer, conversion both from acid to lactone and vice versa is rapid at low pH (<2), and conversion from lactone to acid is predominant at pH > 6 (acid to lactone conversion does not occur at this pH). The instability of the lactone forms at physiologic pH and in plasma has been demonstrated. 13 In addition, as atorvastatin lactone has high affinity for CYP3A4, it has been suggested that the effects of CYP3A4 inhibitors on atorvastatin PK in vivo may be misinterpreted given the interconversion of the acid and lactone demonstrated in vitro .
a Change made for incorporation into lactone model file (file 2). b Assumed to be similar to parent when data not available. c Optimized as explained in Methods Methods 2. Figure 1 Schematic of atorvastatin disposition and modeling strategy. In the disposition schematic, black lines represent clearance processes related to the acid forms, and red arrows represent those of lactone forms. Solid arrows represent the clearance processes of parent acid/lactone, and the dotted lines represent those of the respective hydroxy metabolite.
The intrinsic Fa and fraction escaping metabolism in the gut (Fg) for atorvastatin and atorvastatin lactone were estimated using Simcyp by means of the in vitro measured permeability values and intrinsic clearance values for CYP3A4 metabolism. 14 , 32 Atorvastatin and atorvastatin lactone hepatic metabolism included CYP3A4 and non‐CYP pathways. The CYP3A4‐mediated metabolic intrinsic clearances of atorvastatin and atorvastatin lactone were input from reported in vitro data. 14 Additional non‐CYP microsomal intrinsic clearances were included for atorvastatin and atorvastatin lactone and were adjusted to reproduce the in vivo interaction with itraconazole.
It is reported that atorvastatin lactone can be formed via UGT‐mediated metabolism of atorvastatin acid in the liver, and the reported in vitro intrinsic clearance value for atorvastatin acid lactonization in human liver microsomes (6.2 μL/minute/mg protein) was incorporated as part of the non‐CYP hepatic metabolism of atorvastatin. 9 However, this value is insignificant both with respect to the fraction of all atorvastatin clearance pathways (4%, after accounting for other pathways in the model) and the rapid CYP3A4 intrinsic clearance of atorvastatin lactone (given in Table 1 ), so that atorvastatin lactone was not included as a hepatic metabolite of atorvastatin.
Hence, the elimination was input as human liver microsome intrinsic clearance, and the value was determined from the extended clearance equation 33 using the same optimized o‐hydroxyatorvastatin parameters from the atorvastatin model file. O‐hydroxyatorvastatin lactone was modeled as the primary CYP3A4‐mediated metabolite of atorvastatin lactone, which was presumed to undergo subsequent non‐CYP metabolism in the liver as well as conversion to o‐hydroxyatorvastatin. Systemic conversion of both lactone forms (atorvastatin lactone and o‐hydroxyatorvastatin lactone) back to the respective acid forms was included, as the lactones are unstable in plasma.
42 Based on in vitro data, acid–lactone conversion may occur in either direction at low pH, therefore in the case of simvastatin, dosed in lactone form, increased acid production could occur with delayed gastric emptying, leading to the opposing changes observed in acid and lactone forms. We propose the opposite for atorvastatin, increased lactone production, as it is the acid form of atorvastatin that is administered. A clear limitation of the current model is the inability to truly incorporate reversible metabolism in the current modeling platform (Simcyp v17).
Statins are widely used for treating lipid disorders and cardiovascular diseases. However, the therapeutic efficiency and adverse effects of statins vary among different patients, which numerous clinical and epidemiological studies have attributed to genetic polymorphisms in statin-metabolizing enzymes and transport proteins. The metabolic processes of statins are relatively complex, involving spontaneous or enzyme-catalyzed interconversion between more toxic lactone metabolites and active acid forms in the liver and bloodstream, influenced by multiple factors, including the expression levels of many metabolic enzymes and transporters. Addressing the variable statin therapeutic outcomes is a pressing clinical challenge. Transcription factors and epigenetic modifications regulate the metabolic enzymes and transporters involved in statin metabolism and disposition and, therefore, hold promise as 'personalized' targets for achieving optimized statin therapy. In this review, we explore the potential for customizing therapy by targeting the metabolism of statin medications. The biochemical bases of adverse reactions to statin drugs and their correlation with polymorphisms in metabolic enzymes and transporters are summarized. Next, we mainly focus on the regulatory roles of transcription factors and epigenetic modifications in regulating the gene expression of statin biochemical machinery. The recommendations for future therapies are finally proposed by targeting the central regulatory factors of statin metabolism.
Lactone and acid forms can be converted to each other, and after hepatic metabolism, most are eliminated via bile, and a small portion is excreted via renal pathways ending in urine [ 46 ]. Fig. 2 Metabolism and transportation of statins. Liver uptake transporters take statins from the blood into hepatocytes. In addition, lipophilic statins can be passively transported into hepatocytes. OATPs play an essential role in the uptake of statins to the liver. The metabolic processes of statins include phase I oxidation of CYP450 isoenzymes and phase II glucuronidation mediated by UGT isoenzymes. Glucuronide intermediates are unstable and rapidly decay into lactone forms.
Atorvastatin lactone exhibits a significantly higher affinity for CYP3A4 in human liver microsomes compared to atorvastatin acid, indicating that The majority of acid-form metabolites found in human plasma are produced through the mutual conversion of lactone metabolites, with lactonization being a critical first step in atorvastatin metabolism [ 50 ]. Besides liver metabolism, atorvastatin is also metabolized in the intestine. Atorvastatin lactone shows significant metabolism in human intestine microsomes, with clearance rates at 20 % of those in human liver microsomes [ 51 ].
The mean volume of distribution is approximately 148 L/kg. Pitavastatin is primarily taken up in the liver via OATP1B1, with involvement also from OATP1B3 and NTCP [ [75] , [76] , [77] ]. The CYP450 system has minimal involvement in the metabolism of the compound, with a slight contribution from CYP2C9 [ 78 ], and the drug is primarily excreted unchanged [ 79 ]. The major pathway of pitavastatin metabolism counts on glucuronidation by UGTs to form pitavastatin lactone in the liver. The primary metabolite of pitavastatin in human plasma is lactone, formed by UGT1A3 and UGT2B7 [ 80 ], although UGT2B7-mediated conjugation is rarely observed in other statins [ 45 ].
Clinical studies suggest that polymorphisms in CYP2D6 play a significant role in the efficacy and tolerance of simvastatin [ 92 ]. Although UGT1A1 and UGT1A3 are known to mediate simvastatin lactonization, simvastatin is administered as a lactone. Thus, the simvastatin lactone form detected in the blood is independent of UGT-mediated formation. Simvastatin is also metabolized in the intestine. In human intestinal microsomes, simvastatin lactone exhibited significant metabolism, with intrinsic clearance values corresponding to approximately 20 % of those observed in human liver microsomes [ 51 ]. The study by Deng et al.
The inhibitory effect of the lactone form of statins on the activity of MDR1, CYP2C9, CYP3A4, and CYP3A5 has been found to correlate to lipophilicity, and such inhibition affects drug metabolism, transportation, and interactions [ 110 ]. Ine et al. found that the lactone forms of atorvastatin, fluvastatin, pravastatin, and simvastatin were more toxic to primary human skeletal muscle cells than their acidic forms [ 111 ]. Based on undifferentiated and differentiated C2C12 cells, Taha et al. demonstrated that pH can influence the interconversion between lactone and hydroxy acid forms of simvastatin and pravastatin [ 112 ].
The results indicated that simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatin caused mitochondrial damage in HepG2 cells [ 162 ]. 5.2.2. Cholestasis As the key components of bile, bile acids are produced from cholesterol in the liver through the classical and alternative pathways, creating free primary bile acids. These primary bile acids are combined with taurine, glycine, or sulfate and glucuronic acid to form conjugated bile acids, which are then secreted into the bile ducts to participate in the enterohepatic circulation [ 163 ].
Among the three subtypes PPARα (NR1C1), PPARδ/β (NR1C2), and PPARγ (NR1C3) [ 225 ], PPARα plays a crucial role in the transcriptional regulation of phase II enzymes. PPARα induces the expression of human liver SULT2A1 [ 226 ], and several human liver UGTs, including UGT1A1, UGT1A3, UGT1A4, UGT1A6, and UGT2B4, have shown transcriptional induction in response to PPARα activation [ 227 , 228 ]. Given the crucial role of phase II enzyme UGTs in converting statins into inactive and highly lipophilic lactone forms, PPARα regulation of UGTs is also a possible target for enhancing statin efficacy and reducing adverse effects.
The inhibition of CYP2C9-mediated warfarin metabolism by acid or lactone forms of statin converted in the body and effects of CYP2C9 genetic variants on their inhibition are not fully understood. Here, the effects of acid and lactone forms of statins on S-warfarin 7-hydroxylation were investigated in vitro. S-Warfarin 7-hydroxylase activities of human liver microsomes (HLMs), recombinant CYP2C9.1 (rCYP2C9.1), and rCYP2C9.3 (Ile359Leu variant) in the presence of statins were determined by high-performance liquid chromatography. Lactone forms of atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin inhibited the activity of HLMs more potently than the corresponding acid forms, whereas fluvastatin acid showed stronger inhibition than fluvastatin lactone. When the effects of statins on rCYP2C9 variants were examined, inhibition profiles of acid versus lactone forms of statins except for fluvastatin were similar between rCYP2C9.1 and rCYP2C9.3. However, the degrees of inhibition by atorvastatin lactone, fluvastatin acid, fluvastatin lactone, lovastatin lactone, and pitavastatin lactone (Ki values) were significantly different between these variants. These results indicated that lactone forms of statins other than fluvastatin showed more potent inhibition of CYP2C9-catalyzed S-warfarin 7-hydroxylation than the corresponding acid forms. Furthermore, our results indicated that Ile359Leu substitution in CYP2C9 affected the inhibitory potencies of statins.
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