Drug Invest. 3 IS): 31S-316, 1991 01 I 4-2402/9 l/oooS-03 I S/$Ol.OO/O © Adis International Limited. All rights reserved.

DRI1062

Effects of HMG CoA Reductase Inhibitors on Warfarin Binding

John Feely and Patricia O'Connor Department of Therapeutics and Lipid Clinic, Trinity College Medical School, St James's Hospital, Dublin, Ireland

Inhibitors of 3-hydroxy-3-methylglutaryl coen­zyme A (HMG CoA) reductase such as lovastatin, simvastatin and pravastatin reduce cholesterol lev­els by up to 40% (O'Connor et aL 1990) and are now in widespread use. Both lovastatin (Bilheimer 1990) and simvastatin (Todd & Goa 1990) have been reported to increase prothrombin time in patients taking concomitant coumarin or antico­agulants such as warfarin, and there have been re­ports of epistaxis, haematuria and gastrointestinal bleeding consequent to this interaction (Ahmad 1990). In contrast, no such interaction has been seen with pravastatin (LaRosa 1989), As both 10-vastatin and simvastatin are highly bound in plasma to albumin (> 95%) and the binding ofpra­vastatin is in the region of 55%, it has been sug­gested (LaRosa 1989) that differences in protein binding may account for differences in the inci­dence of interactions with warfarin. We therefore compared the protein binding of warfarin before and during treatment with simvastatin or pravas­tatin in 34 hypercholesterolaemic patients.

Patients and Methods

34 patients (19 female) aged 53 ± 5 years (mean ± SEM) with primary hypercholesterolaemia (total serum cholesterol level > 6.5 mmolfL) received, over 12 weeks, increasing doses of simvastatin 10 to 40mg (n = 21) or pravastatin 20 to 40mg (n = 13) until serum cholesterol was < 6.5 mmolfL. All

patients were maintained on a standard low chol­esterol diet throughout the study, and no patient received any other drug known to influence the protein binding of warfarin. All patients were stud­ied following an overnight fast.

Blood was collected by direct venipuncture into glass tubes and centrifuged. Serum protein binding was determined at 37T by equilibrium dialysis us­ing semi macrocells (Dianorm 1 ml) and a semi­permeable membrane with molecular cutoff of 10 000 (Medicell International Ltd). Stability was achieved as previously described by Bmrs and Ja­cobsen (1985). Serum was separated by the mem­brane from a similar volume of buffer (Na2HP04/ KH2P04), pH 7.45, containing 14C warfarin (Amersham) at a concentration of 2 mg/L. After equilibrium for 4 hours, 500!Ll aliquots were taken from both chambers and radioactivity was deter­mined in a liquid scintillation counter. The per­centage of unbound drug was calculated as a ratio of the absolute disintegration rates in buffer and serum. All samples were measured in duplicate with a coefficient of variation of less than 5%.

Statistical analysis was by paired Student t-test.

Results

After 12 weeks' treatment, mean serum chol­esterollevels fell from 8.8 ± 1.2 mmolfL to 5.9 ± 0.8 mmol/L (p < 0.001). The free concentration of

SHORT COM MUNICATION

316

Table I. Percentage of free concentration Of warfarin (mean ± SEM)

Treatment Warfarin (%)

Control 1.56 ± 0.04 Simvastatin 1.60 ± 0.04 Control 1.55 ± 0.05 Pravastatin 1.53 ± 0.04

warfarin did not change during treatment with either simvastatin or pravastatin (table I).

Discussion

To date, interactions involving HMG CoA re­ductase inhibitors have been relatively few. The most clinically significant interaction is myopathy, which occurs when these agents are used in com­bination with gemfibrozil, nicotinic acid or cyclo­sporin. Combined use with cyclosporin may pro­duce myopathy in up to 30% of patients and, in addition, rhabdomyolysis with renal failure has also been reported (East et al. 1988). A direct toxic ef­fect on muscle creatinine phosphokinase appears to be responsible for this toxicity. As HMG CoA reductase inhibitors are metabolised in the liver, their potential effect on hepatic drug metabolism has been examined. Neither pravastatin (Mc­Tavish & Sorkin 1991), simvastatin (Todd & Goa 1990), nor lovastatin (Grundy 1988) have an effect on cytochrome P-450, as assessed from antipyrine clearance. In contrast, propranolol appears to re­duce the oral bioavailability of both lovastatin and pravastatin (Pan et al. 1991); however, the clinical consequence of this interaction has not been re­ported and is not likely to be large.

Lovastatin and simvastatin may enhance the anticoagulant effect of warfarin, but this mechan­ism remains to be established. A study in healthy

Drug Invest. 3 (5) 1991

volunteers maintained in a state oflow therapeutic anticoagulation suggested a small « 2 sec) pro­longation of prothrombin time. However, no de­tails were given with regard to the effect on the clearance of warfarin or its different isomers. From our data, it is clear that therapeutic doses of sim­vastatin and pravastatin that produce a hypocho­lesterolaemic effect do not alter the extent of plasma protein binding of warfarin. While the exact mech­anism of this interaction remains to be elucidated, it is possible that displacement at tissue binding sites for warfarin is responsible.

References

Ahmad S. Lovastatin warfarin interaction. Archives of Internal Medicine 150: 2407, 1990

Bilheimer DW. Long term clinical tolerance of lovastatin (mev­inolin) and simvastatin (epistatin). An overview. Drug Inves­tigation 2 (Suppl. 2): 58-67, 1990

Bmrs 0, Jacobsen S. pH lability in serum during equilibrium dialysis. British Journal of Clinical Pharmacology 20: 85-88. 1985

East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA. Rhab­domyolysis in patients receiving lovastatin after cardiac trans­plantation. New England Journal of Medicine 318: 47-48, 1988

Grundy SM. HMG-CoA reductase inhibitors for treatment of hy­percholesterolemia. New England Journal of Medicine 319: 24-32, 1988

LaRosa Jc. Pravastatin: a new hydrophilic HMG-CoA-reductase inhibitor. In LaRosa (Ed.) New advances in the control oflipid metabolism: focus on pravastatin. Royal Society of Medicine Services International Congress and Symposium Series No. 162, 39-43, 1989

McTavish D, Sorkin EM. Pravastatin: a review of its pharma­cological properties and therapeutic potential in hyperchol­esterolaemia. Drugs 42 (1): 65-89, 1991

O'Connor P, Feely J, Shepherd J. Lipid lowering drugs. British Medical Journal 300: 667-672, 1990

Pan HY, Triscari J, deVault AR, Smith SA, Wang-Iverson D, et al. Pharmacokinetic interaction between propranolol and the HMG-Co A Reductase inhibitors pravastatin and lovastatin. British Journal of Clinical Pharmacology 31: 665-670, 1991

Todd PA, Goa KL. Simvastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs 40 (4): 583-607, 1990

Correspondence and reprints: Prof. John Feely. Department of Pharmacology and Therapeutics, Trinity College Medical School, St James's Hospital, Dublin 8, Ireland.