Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Für die Kombination von Sirolimus und Cimetidin liegen uns keine zusätzlichen Warnhinweise vor. Bitte konsultieren Sie zusätzlich die jeweiligen Fachinformationen.
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Die Exposition von Sirolimus erhöht sich auf 103%, wenn eine Kombination mit Cimetidin (103%) erfolgt. Eine Veränderung der Exposition von Cimetidin haben wir nicht erkannt. Den Einfluss von Sirolimus können wir aktuell nicht abschätzen.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Sirolimus hat eine tiefe orale Bioverfügbarkeit [ F ] von 14%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell stark verändern. Die terminale Halbwertszeit [ t12 ] ist mit 75 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 300 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 92% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 224 Liter sehr gross. da die Substanz eine tiefe hepatische Extraktionsrate von 0.02 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP. Unter anderem ist Sirolimus ein Hemmer von BCRP und PGP.
Cimetidin hat eine mittlere orale Bioverfügbarkeit [ F ] von 65%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 1.6333333 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 19% sehr schwach und das Verteilungsvolumen [ Vd ] ist mit 91 Liter sehr gross. Die Metabolisierung erfolgt nicht über die gängigen Cytochrome und der aktive Transport erfolgt zum Teil über BCRP und PGP. Unter anderem ist Cimetidin ein Hemmer von CYP3A4.
|Serotonerge Effekte a||0||Ø||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöhen weder Sirolimus noch Cimetidin die serotonerge Aktivität.
|Kiesel & Durán b||1||Ø||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Cimetidin beeinflusst das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet. Gemäss unseren Erkenntnisse erhöht Sirolimus nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Empfehlung: Bitte achten Sie darauf, dass beeinflussbare Risikofaktoren minimiert werden. Elektrolytstörungen, wie tiefe Werte von Calcium, Kalium und Magnesium sollten ausgeglichen werden. Die niedrigst wirksame Dosis von Cimetidin sollte eingesetzt werden.
Bewertung: Cimetidin kann potentiell die QT-Zeit verlängern und bei Vorliegen von Risikofaktoren können Arrhythmien vom Typ Torsades de pointes begünstigt werden. Für Sirolimus ist uns kein QT-Zeit verlängerndes Potential bekannt.
|Erhöhtes Serumkreatinin||39.5 %||39.5||n.a.|
Stomatitis (20%): Sirolimus
Myalgie (20%): Sirolimus
Schwindel (20%): Sirolimus
Progressive multifokale Leukoenzephalopathie: Sirolimus
Nasopharyngitis (20%): Sirolimus
Infektion der oberen Atemwege (20%): Sirolimus
Nasenbluten (6%): Sirolimus
Interstitielle Lungenentzündung (5.3%): Sirolimus
Interstitielle Lungenerkrankung: Sirolimus
Periphere Ödeme (19%): Sirolimus
Hautausschlag (15%): Sirolimus
Basalzellkarzinom der Haut: Sirolimus
Thrombotische thrombozytopenische Purpura (11.5%): Sirolimus
Venöse Thromboembolie (11.5%): Sirolimus
Gynäkomastie (4%): Cimetidin
Lymphom (3.2%): Sirolimus
Hämolytisch-urämisches Syndrom: Sirolimus
Nephrotisches Syndrom: Sirolimus
Basierend auf Ihren
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: Small intestinal metabolism and transport of sirolimus, a macrolide immunosuppressant with a low and highly variable oral bioavailability, were investigated using small intestinal microsomes and intestinal mucosa in the Ussing chamber. After incubation of sirolimus with human and pig small intestinal microsomes, five metabolites were detected using high performance liquid chromatography/electrospray-mass spectrometry: hydroxy, dihydroxy, trihydroxy, desmethyl and didesmethyl sirolimus. The same metabolites were generated by human liver microsomes and pig small intestinal mucosa in the Ussing chamber. Anti-CYP3A antibodies, as well as the specific CYP3A inhibitors troleandomycin and erythromycin, inhibited small intestinal metabolism of sirolimus, confirming that, as in the liver, CYP3A enzymes are responsible for sirolimus metabolism in the small intestine. Of 32 drugs tested, only known CYP3A substrates inhibited sirolimus intestinal metabolism with inhibitor constants (Ki) equal to those in human liver microsomes. The formation of hydroxy sirolimus by small intestinal microsomes isolated from 14 different patients ranged from 28 to 220 pmol.min-1.mg-1 microsomal protein. In the Ussing chamber, >99% of the sirolimus metabolites reentered the mucosa chamber against a sirolimus gradient, indicating active countertransport. Intestinal drug metabolism and countertransport into the gut lumen, drug interactions with CYP3A substrates and inhibitors in the small intestine and an 8-fold interindividual variability of the intestinal metabolite formation rate significantly contribute to the low and highly variable bioavailability of sirolimus.
Abstract: Sirolimus (previously known as rapamycin), a macrocyclic lactone, is a potent immunosuppressive agent. Sirolimus was recently approved by the US Food and Drug Administration, on the basis of 2 large, double-blind, prospective clinical trials, for use in kidney transplant recipients at a fixed dosage of 2 or 5 mg/day in addition to full dosages of cyclosporin and prednisone. However, despite the fixed dosage regimens used in these pivotal trials, pharmacokinetic and clinical data show that sirolimus is a critical-dose drug requiring therapeutic drug monitoring to minimise drug-related toxicities and maximise efficacy. Assays using high performance liquid chromatography coupled to mass spectrometry, although cumbersome, are the gold standard for evaluating other commonly used assays, such as liquid chromatography with ultraviolet detection, radioreceptor assay and microparticle enzyme immunoassay. Sirolimus is available in oral solution and tablet form. It has poor oral absorption and distributes widely in tissues, displaying not only a wide inter- and intrapatient variability in drug clearance, but also less than optimal correlations between whole blood concentrations and drug dose, demographic features or patient characteristics. Furthermore, the critical role of the cytochrome P450 3A4 system for sirolimus biotransformation leads to extensive drug-drug interactions, among which are increases in cyclosporin concentrations. Thus, sirolimus is now being used to reduce or eliminate exposure to cyclosporin or corticosteroids. The long elimination half-life of sirolimus necessitates a loading dose but allows once daily administration, which is more convenient and thereby could help to improve patient compliance. This review emphasises the importance of blood concentration monitoring in optimising the use of sirolimus. The excellent correlation between steady-state trough concentration (at least 4 days after inception of, or change in, therapy) and area under the concentration-time curve makes the former a simple and reliable index for monitoring sirolimus exposure. Target trough concentration ranges depend on the concomitant immunosuppressive regimen, but a range of 5 to 15 microg/L is appropriate if cyclosporin is being used at trough concentrations of 75 to 150 microg/L. Weekly monitoring is recommended for the first month and bi-weekly for the next month; thereafter,concentration measurements are necessary only if warranted clinically.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
Abstract: Sirolimus is a recently marketed immunosuppressant that, in common with cyclosporine and tacrolimus, exhibits a low average oral bioavailability (approximately 20%). Likewise, sirolimus is a substrate for the major drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp), both of which are expressed in close proximity in epithelial cells lining the small intestine. Using CYP3A4-expressing Caco-2 cell monolayers, we examined the interplay between metabolism and transport on the intestinal first-pass extraction of sirolimus. Modified Caco-2 cells metabolized [14C]sirolimus to the same CYP3A4-mediated metabolites as human small intestinal and liver microsomes. [14C]Sirolimus also degraded to the known ring-opened product, seco-sirolimus. A ring-opened dihydro species (M2) was, surprisingly, the major product detected in cells at all sirolimus concentrations examined (2-100 micromol/L) and in incubations with human liver and intestinal homogenates but not in corresponding microsomes. M2 formation was NADPH-dependent but unaffected by prototypical CYP3A4 inhibitors. Although M2 was formed from purified seco-sirolimus (20 micromol/L) in the homogenates, it was not detected in cells when seco-sirolimus was added to the apical compartment because seco-sirolimus was essentially impermeable to the apical membrane. Sirolimus, seco-sirolimus (basolaterally dosed), and M2 were all secreted across the apical membrane, and secretion of each was inhibited by the P-gp inhibitor LY335979 (zosuquidar trihydrochloride). Along with CYP3A4-mediated metabolism and P-gp-mediated efflux, a novel elimination pathway was identified that may also contribute to the first-pass extraction, and hence low oral bioavailability, of sirolimus. This new insight into the intestinal elimination of sirolimus, which was not identified using traditional drug metabolism/transport screening methods, may represent another source for the limited absorption of sirolimus.
Abstract: The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: Previous studies have shown that rapamycin can inhibit the growth of several different types of human tumor cells in vitro. In certain cases, it can reverse the phenotype of multidrug resistant (MDR) cells. However, there is limited information concerning its effect on P-glycoprotein (P-gp), a pump that is responsible for chemoresistance in many MDR cells. We investigated the effect of rapamycin on both P-gp function and the MDR phenotype in four cell lines. One cell line was also xenografted into SCID mice to determine whether rapamycin would chemosensitize the cells in vivo. Because rapamycin targets the mammalian target of rapamycin (mTOR) pathway, we also used our cells to confirm that rapamycin modified the expression of mTOR and effectively suppressed the phosphorylation of two downstream effector molecules in the mTOR pathway, S6K1, and 4E-BP1. We demonstrated that it inhibited the growth of the three cell lines in vitro and one in vivo showing that it modulated both the expression and function of P-gp and chemosensitized the three cell lines as effectively as verapamil.
Abstract: PURPOSE: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models. EXPERIMENTAL DESIGN: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined. RESULTS: Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma. CONCLUSION: Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.
Abstract: Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is increasingly being used in transplantation and cancer therapies. Sirolimus has low oral bioavailability and exhibits large pharmacokinetic variability. The underlying mechanisms for this variability have not been explored to a large extent. Sirolimus metabolism was characterized by in vitro intrinsic clearance estimation. Pathway contribution ranked from CYP3A4 > CYP3A5 > CYP2C8. With the well stirred and Qgut models sirolimus bioavailability was predicted at 15%. Interindividual differences in bioavailability could be attributed to variable intestinal CYP3A expression. The physiologically-based pharmacokinetics (PBPK) model developed in Simcyp predicted a high distribution of sirolimus into adipose tissue and another elimination pathway in addition to CYP-mediated metabolism. PBPK model predictive performance was acceptable with Cmax and area under the curve (AUC) estimates within 20% of observed data in a dose escalation study. The model also showed potential to assess the impact of hepatic impairment and drug-drug interaction (DDI) on sirolimus pharmacokinetics.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e59; doi:10.1038/psp.2013.33; published online 24 July 2013.
Abstract: This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration-time curves (AUC) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (C) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cof mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: BACKGROUND: Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A4*1G and CYP3A5*3 polymorphisms, on the pharmacokinetics of sirolimus. METHODS: Thirty-one healthy Chinese volunteers were included in this study. Their genotypes were determined using the Sequenom MassARRAY iPLEX platform, and blood sirolimus concentrations at different time points were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using WinNonlin version 5.2 software. RESULTS: The allele frequencies of CYP3A4*1G and CYP3A5*3 were 25.8% and 71.0%, respectively. In CYP3A4*1G carriers (n = 13), the area under the curve AUC0-144, AUC0-∞, and Cmax were significantly lower (P < 0.05) than CYP3A4*1/*1 homozygous subjects (n = 18). Briefly, the AUC0-144, AUC0-∞, and Cmax of *1G/*1G carrier were 315.2 ± 91.5, 372.0 ± 108.2, and 10.2 ± 1.6 ng/mL, respectively, and those of *1/*1 G*1/*1 G carrier were 440.8 ± 130.6, 537.4 ± 167.5, and 13.7 ± 4.3, respectively, whereas those of CYP3A4*1/*1 homozygous subjects were 540.2 ± 150.6, 626.6 ± 166.9, and 19.8 ± 7.5 ng/mL, respectively. In CYP3A5-nonexpressing subjects (*3/*3 homozygous carriers, n = 15), the AUC0-144 and Cmax were 549.6 ± 137.9 and 19.9 ± 7.9 ng/mL, respectively, and were significantly higher (P < 0.05) than the values in CYP3A5-expressing subjects (*1/*1homozygous carrier, n = 2; 314.2 ± 129.3 and 10.3 ± 2.2 ng/mL; *1/*3 heterozygous carrier, n = 15; 440.2 ± 146.3 and 14.6 ± 5.1 ng/mL, respectively). CONCLUSIONS: CYP3A4 and CYP3A5 genetic polymorphisms are important factors affecting pharmacokinetic parameters of sirolimus. Our data support the monitoring of blood sirolimus concentrations, especially in CYP3A5*1 and CYP3A4*1 G carriers, to ensure accurate dosing in the clinical setting.