Lipid-lowering therapy with statins improves survival and decreases complications in patients with coronary artery disease . It is likely that males with elevated plasma cholesterol concentrations, but without diagnosed coronary artery disease, may benefit from long-term statin therapy. Hence, anaesthetists should expect that more adults presenting for surgery in the future would be taking these drugs.
Individual statins, including atorvastatin, simvastatin and lovastatin, are metabolized primarily by the CYP3A4 isoform of the cytochrome (CYP) P450 system . In general, phase 1 metabolism comprises oxidation, reduction or hydrolysis, of which the former is usually catalysed by these enzymes located primarily in the liver . This family of enzymes is classified as CYP1, CYP2 and CYP3, each of which is further classified on the basis of substrate selectivity . Of the 60 isoforms identified, CYP3A4 catalyses the metabolism of several intravenous anaesthetic agents. There is therefore a potential for pharmacokinetic drug interactions to occur between these statins and other agents that are metabolized by, or inhibit, CYP3A4 . Most patients who undergo surgery under general anaesthesia receive an opioid, benzodiazepine or other intravenous anaesthetic agent. CYP3A4 contributes to the metabolism of fentanyl and sufentanil  and is the only isoform known to catalyse the conversion of alfentanil to noralfentanil .
Our hypothesis was that potentially important pharmacokinetic drug interactions between alfentanil and atorvastatin could result in altered pharmacokinetics of alfentanil during the perioperative period. In order to test this hypothesis, we examined the pharmacokinetic profiles of alfentanil in patients currently receiving atorvastatin to whom infusions of alfentanil are administered.
The study was approved by our Institutional Ethics Committee, and written informed consent was obtained from all subjects. Sixteen ASA I-II patients (35-75 yr) scheduled to undergo elective surgery requiring general anaesthesia were studied. Eight patients were currently receiving atorvastatin for at least 4 months and eight patients were not receiving the drug. Patients were matched as pairs for age, gender and body mass index. Matching comprised selecting pairs such that the greater value for age and body mass index in each pair was within 10% of the lesser value.
Exclusion criteria were concurrent or recent medication with opioids, benzodiazepines or an agent known to influence P450 activity, liver disease, obesity (body mass index > 30 kg m−2) or indication for rapid sequence induction of anaesthesia. Other exclusion criteria included intake of coffee or alcohol (in the preceding 24 h) and intake of grapefruit, grapefruit juice or macrolide antibiotics (in the preceding 7 days) before enrolment.
The following information was sought from patients taking atorvastatin: daily dosage, duration of administration, time of administration and, if laboratory blood tests were monitored, for muscle and liver function.
No premedication was given. Atorvastatin administration was continued until and including the morning of surgery. Two intravenous cannulae (one 16/18-G cannula dedicated to withdrawal of venous samples) were inserted and standard monitoring (pulse oximetry, electrocardiography, non-invasive blood pressure) was applied. Anaesthesia was induced with a bolus of sodium thiopental (1-1.5 mg kg−1 i.v.) immediately followed by an alfentanil bolus (80 μg kg−1 i.v.) over 60 s. Muscle relaxation was achieved using pancuronium (0.06 mg kg−1 i.v.). Upon completion of the alfentanil bolus, an infusion of alfentanil (0.67 μg kg min−1 i.v.) was commenced immediately and maintained for 90 min. Metoclopramide (10 mg i.v.) and tenoxicam (20 mg i.v.) were administered intraoperatively. Sevoflurane (PET 0.7-1.5%) was administered in a mixture of nitrous oxide (60%) and oxygen, and intermittent positive pressure ventilation of the lungs was adjusted to maintain normocapnia. In the postoperative recovery area, morphine (0.05-0.1 mg kg−1 i.m.) was administered if supplemental analgesia was requested. Body temperature was monitored using a nasopharyngeal thermistor probe and readings were taken at the start of surgery, at the termination of the infusion and at the end of surgery. All patients were actively warmed with a forced air warming blanket (Bair Hugger® Warming Unit, Model 505; Mallinckrodt Medical, Inc., Cd. Juarez, Chih., Mexico).
Venous blood samples were withdrawn for alfentanil analysis at 30 and 60 min intervals after commencing the infusion (T1-T2), at discontinuation of the infusion (T3) and at 45 min intervals thereafter for 6 h (T4-T10). Venous blood was also withdrawn before induction and 24 h later for measurement of plasma concentrations of urea, creatinine and creatine phosphokinase (CPK).
Patients were observed for at least 4 h postoperation and discharged to the ward based on a clinical assessment of ventilatory function and sedation. During the first 24 h of the postoperative period, the patient was closely monitored for hypotension, bradycardia, respiratory depression, sedation and myalgia.
Plasma alfentanil concentrations were measured using a gas chromatographic-nitrogen phosphorous detection assay . Analysis was performed by Tepnel Scientific Services (West of Scotland Science Park, Glasgow, UK), using an HP 5890® series II gas chromatograph together with a HP 7673® autoinjector (Hewlett Packard, Palo Alto, CA, USA). Calibration curves were linear with an intercept near the origin. Intrabatch imprecision ranged from 3.25% at 200 ng mL−1 to 12.9% at 1 ng mL−1, whilst intrabatch inaccuracy ranged from 10.57% at 200 ng mL−1 to 0.22% at 1 ng mL−1. Within-batch imprecision and inaccuracy were <20% at the lower limit of quantification and 15% at the upper limit of quantification. Any samples measured above the upper limit of quantification were diluted and reassayed and found to be within 15% of the initial value obtained.
Statistical and pharmacokinetic analyses
Patients' characteristics data, fluid and alfentanil administration, and pre- and postoperative biochemical variables were analysed using paired t-tests. Statistical significance was set at P < 0.05 and all results are the mean (±SD).
The power analysis for this study was based on α = 0.05 and β = 0.2. The effect size examined was for a 40% increase in the elimination half-life of alfentanil. The value of 97 min with a SD of 22 was taken from Meistelman and colleagues . The minimum sample size, calculated for this matched pair study, was six pairs.
Alfentanil plasma concentration-time data for each patient at all time points were analysed using the ABBOTTBASE® Pharmacokinetic Systems software, version 1.10 (Abbott Diagnostics, Abbott Park, IL, USA). The area under the curve (AUC) and area under the moment curve (AUMC) was calculated using the trapezoidal rule (non-compartmental analysis). Weighted log-linear regression analysis was used to estimate the elimination half-life from at least the last three time points of the terminal phase of decline. Plasma clearance (CL) and Vdss of alfentanil were calculated by non-compartmental methods based on statistical moment theory . Based on the data thus obtained, a comparison of pharmacokinetic parameters between both groups was made using one-tailed, paired t-tests. P < 0.05 was taken as statistically significant.
The two groups were similar in terms of age, weight, duration of fasting, duration of surgery and total alfentanil consumption (Table 1). In the control group, two patients underwent general surgery, two patients underwent urological surgery, one patient underwent orthopaedic surgery, one patient underwent gynaecological surgery and one patient underwent ophthalmic surgery. In the atorvastatin group, three patients underwent general surgery, two patients underwent urological surgery and two patients underwent ophthalmic surgery.
Four patients were taking the 10 mg formulation and three patients were taking the 20 mg formulation of atorvastatin. The duration of atorvastatin administration was 7.2 months (range 4-12 months). All patients chronically self-administered atorvastatin at approximately the same time of day (21:00-23:00 h). Only one patient had liver function tests and plasma creatine phosphokinase monitored since commencing statin therapy. No patient complained of gastrointestinal or muscular side-effects since commencing atorvastatin. Three of the seven statin patients demonstrated preoperative alkaline phosphatase concentrations above the upper limit of normal (>130 IU L−1). Two of those four patients also had preoperative alanine aminotransferase concentrations elevated above the upper limit of normal (>36 UL−1). In the control group, one patient had an elevated preoperative alkaline phosphatase concentration. Increased values of liver function tests are a common side-effect of statin therapy and there was no statistically significant difference between the two groups for these variables.
There was a statistically significant increase in the postoperative creatine phosphokinase concentration in the control group compared with the statin group. Two patients within the control group underwent surgical procedures that were more invasive than for other patients in this study (radical nephrectomy and radical prostatectomy). Both patients demonstrated postoperative creatine phosphokinase concentrations >1200 U L−1 (upper limit of normal = 140 U L−1) and contributed disproportionately to the overall mean value for postoperative creatine phosphokinase in this group.
In four of the 16 patients, the alfentanil infusion was terminated before 90 min as surgery had finished. One matched pair received an 80 min infusion and one matched pair received a 30 min infusion. In these patients, a sample was withdrawn immediately before discontinuing the infusion. Subsequent samples were withdrawn at 45 min intervals as with all other patients.
The volume of crystalloid administration in the control group was 2.6 (±1.8) and 1.6 (±0.9) L in the atorvastatin group. As a result of significant intraoperative blood loss (2.8 and 1.9 L), two patients were transfused with blood (4 and 2 units packed red cells, respectively). Both patients were in the control group. The blood loss in all the other patients in the study was <500 mL.
The nasopharyngeal temperature was similar in the two groups at the start of surgery (36.4 versus 35.9°C), at the end of infusion (36.0 versus 35.7°C) and at the end of surgery (36.2 versus 35.8°C).
No episodes of chest wall stiffness or bradycardia (heart rate < 50 beats min−1) were recorded. Two patients experienced hypotension (decrease in mean arterial pressure > 20% from baseline) on induction of anaesthesia requiring treatment with ephedrine (6 mg) and crystalloid infusion. Each patient promptly recovered to within 20% of the preoperative baseline arterial pressure and no further episodes of hypotension were recorded. No episodes of hypotension or myalgia were documented postoperation. TABLE
The elimination half-life (t1/2β) in the control group (n = 7) was 98.8 versus 98.3 min for the atorvastatin group. The area under the curve (AUC), clearance (Cl) and volume of distribution under steadystate conditions (Vdss) in the control group were 0.05 mg min mL−1, 0.20 L min−1 and 0.38 L kg−1, respectively, versus 0.04 mg min mL−1, 0.22 L min−1 and 0.39 L kg−1, respectively, in the atorvastatin group (Table 3). For each of these parameters, the values were consistent in both groups with values previously reported. The data describing the plasma alfentanil-time relationship are depicted graphically in Fig. 1.
Patient 3 (a control patient) received erythromycin 1 g intraoperatively. This macrolide antibiotic is a potential CYP3A4 inhibitor and preoperative macrolide antibiotics were considered an exclusion criterion for this protocol. For this reason, this patient and the corresponding match were excluded from analysis of all data leaving seven matched pairs remaining in this study.
The most important finding of this study is that concurrent atorvastatin therapy does not alter the pharmacokinetic profile of alfentanil administered by infusion to patients undergoing elective surgery.
The metabolism of alfentanil by P450 represents an important site for potential drug interaction and inhibition of drug metabolism. CYP3A4 is the major isoform of P450 responsible for clinical alfentanil metabolism and clearance . The synthetic opioid alfentanil undergoes extensive metabolism via two major pathways: piperidine nitrogen dealkylation to noralfentanil and amide nitrogen dealkylation to N-phenylpropionamide . Using human liver microsomes, significant amide N-dealkylation of alfentanil, but not of noralfentanil, was observed, indicating that N-phenylpropionamide is derived directly from alfentanil and is not a secondary metabolite of noralfentanil . Therefore, P4503A4 plays a significant role in both major pathways of fentanyl metabolism.
Atorvastatin is also metabolized by CYP3A4 and this therefore represents a potential site of drug interaction with alfentanil. Metabolism of atorvastatin acid and lactone by human liver microsomes results in corresponding para- and ortho-hydroxy metabolites . In this study, atorvastatin was administered in its acid form, as is standard clinical practice. Both acid and lactone forms are metabolized mainly by CYP3A4 and CYP3A5. In an in vitro study using human liver microsomes, the lactone had a significantly greater affinity to CYP3A4 than the acid. This study also demonstrated the lactone to be a more potent inhibitor of CYP3A4 function than the acid form . The extent of conversion from acid to lactone that takes place following oral administration of atorvastatin is unknown.
CYP3A4 inhibitors decrease the rate of metabolism of alfentanil . The clinical consequences of such an interaction are important because of the short half-life of alfentanil and the high plasma concentration achieved during anaesthesia. Normally, rapid elimination decreases plasma concentrations to a point below which clinically significant respiratory depression does not occur. Therefore, any drug interaction that decreases the metabolism and clearance of alfentanil could cause respiratory depression. For instance, the elimination half-life for alfentanil was almost doubled when co-administered with either oral or intravenous fluconazole, and alfentanil-induced depression of respiratory rate was increased by 10-15% [16,17].
Co-administration of atorvastatin with potent CYP3A4 inhibitors significantly increases plasma atorvastatin concentrations. An increased risk of rhabdomyolysis has been reported after concomitant use of lovastatin and simvastatin with cyclosporine, erythromycin and itraconazole , all of which are potent CYP3A4 inhibitors. The mechanism of development of rhabdomyolysis in these cases is not known, but is thought to be related to high local statin concentrations and a direct effect of HMG Co-A reductase inhibition. Previous studies have demonstrated an overall 1% incidence rate of rhabdomyolysis, defined as creatine phosphokinase >10 times the upper limit of normal, and muscle symptoms with statin administration . In the present study, nine patients (seven control and two atorvastatin patients) demonstrated postoperative CPK concentrations >140 UL−1 (the upper limit of normal). The duration of surgery was greater in the control patients. Of these nine patients, one demonstrated an increase in CPK of 10 times above the upper limit of normal (in whom the duration of surgery was 300 min).
This is the first trial to investigate the effects of atorvastatin on the pharmacokinetics of an intravenous anaesthetic agent. To increase the likelihood of identifying such an effect (if one truly exists), a high dose of alfentanil was administered (80 μg kg−1 intravenous bolus followed by infusion of 0.67 μg kg−1 min−1 for 90 min). Although the number of patients studied was small (n = 14), comparisons were made between pairs of patients matched for potential confounding factors (e.g. age, gender, body mass index).
In this study, the concurrent administration of atorvastatin demonstrated no inhibition of the metabolism of alfentanil and we conclude that atorvastatin does not affect the pharmacokinetics of alfentanil in the dose range examined in the present study.
1. Erikssen J, Madsen S. Treatment of hypercholesterolemia with statins. Tidsskr Nor Laegeforen
2. Prueksaritanont T, Gorham LM, Ma B, et al. In vitro
metabolism of simvastatin in humans [SBT] identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos
3. Chang GWM, Kam PCA. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia
4. Nelson DR, Koymans L, Kamtaki T, et al.
P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics
5. Segaert MF, De Soete C, Vandwiele I, Verbanck J. Drug interaction-induced rhabdomyolysis. Nephrol Dial Transplant
6. Guitton J, Buronfosse T, Desage M, et al.
Possible involvement of multiple cytochrome P450s in fentanyl and sufentanil metabolism as opposed to alfentanil. Biochem Pharmacol
7. Labroo RB, Thummel KE, Kunze KL, Podoll T, Trager WF, Kharasch ED. Catalytic role of cytochrome P450 3A4 in multiple pathways of alfentanil metabolism. Drug Metab Dispos
8. Janicki PK, James MFM, Erskine WAR. Propofol inhibits enzymatic degradation of alfentanil and sufentanil by isolated liver microsomes in vitro. Br J Anaesth
9. Meistelman C, Saint-Maurice C, Lepaul M. A comparison of alfentanil pharmacokinetics in children and adults. Anesthesiology
10. Gibaldi M, Perrier D. Pharmacokinetics,
2nd edn. New York, USA: Marcel Dekker, 1982.
11. Kharasch ED, Russell M, Mautz D, et al.
The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions. Anesthesiology
12. Meuldermans W, Van Peer A, Hendrickx J, et al.
Alfentanil pharmacokinetics and metabolism in humans. Anesthesiology
13. Michniewicz BM, Black AE, Sinz MW, et al. In vitro
and in vivo
metabolism of atorvastatin (CI-981). ISSX Proc
14. Ishigami M, Hoda T, Takasaki W, et al.
A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on the CYP 3A4-dependent oxidation of mexazolam in vitro. Drug Metab Dispos
15. Bartkowski RR, Goldberg ME, Larijani GE, Boerner T. Inhibition of alfentanil metabolism by erythromycin. Clin Pharmacol Ther
16. Palkama VJ, Isohanni MH, Neuvonen PJ, Olkkola KT. The effect of intravenous and oral fluconazole on the pharmacokinetics and pharmacodynamics of intravenous alfentanil. Anesth Analg
17. Penon C, Negre I, Ecoffey C, Gross JB, Levron JC, Samii K. Analgesia and ventilatory response to carbon dioxide after intramuscular and epidural alfentanil. Anesth Analg
18. Maltz HC, Balog DL, Cheigh JS. Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine. Ann Pharmacother
19. Norman DJ, Illingworth DR, Munson J, Hosenpud J. Myolysis and acute renal failure in a heart-transplant patient receiving lovastatin. N Engl J Med