El color usando Coordenadas L*a*b*

A 63-year-old dentist had been taking phenytoin (Dilantin), 400 mg/day (blood level, generally 13–15 µg/mL) for 25 years to treat his seizure dis- order. He began to develop chronic indigestion pain, and he made an ap- pointment with his internist to address this complaint. His internist pre- scribed ranitidine (Zantac), 150 mg bid. Over the course of the next week, the patient experienced increasing dizziness, difficulty concentrating, and tremor. These symptoms became so severe that he cancelled his workday for fear that he would hurt a patient by slipping during a procedure. He contacted his internist, who instructed the patient to report to the local emer- gency room for a stat phenytoin blood level, which was 21.8 µg/mL. His in- ternist instructed him to immediately stop his ranitidine, and his symptoms remitted within 2 days of doing so.

Discussion

This is an example of an inhibitor added to a substrate.

Phenytoin is mostly a substrate of 2C9 and 2C19 (Cadle et al. 1994; Mamiya et al. 1998), and ranitidine is (probably) a mild to moderate inhib- itor of both 2C9 and 2C19 (Bramhall and Levine 1988; Tse et al. 1993). Thus, the addition of ranitidine led to an impairment in the ability of 2C9 and 2C19 to contribute to the metabolism of phenytoin. This inhibition caused the blood level of phenytoin to increase, even though there had been no increase in the dosage of phenytoin (Tse et al. 1993).

Ranitidine is considered to pose minimal risks for drug interactions. It is certainly much less generally a culprit than the pan-inhibitor cimetidine (Tagamet). However, individual cases have demonstrated that the addition of ranitidine to phenytoin can increase phenytoin blood levels by roughly 40% (Bramhall and Levine 1988).

References

Bramhall D, Levine M: Possible interaction of ranitidine with phenytoin. Drug Intell Clin Pharm 22:979–980, 1988

Cadle RM, Zenon GJ 3rd, Rodriguez-Barradas MC, et al: Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother 28:191–195, 1994 Mamiya K, Ieiri I, Shimamoto J, et al: The effects of genetic polymorphisms of

CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharma- cokinetics. Epilepsia 39:1317–1323, 1998

Tse CS, Akinwande KI, Biallowons K: Phenytoin concentration elevation subse- quent to ranitidine administration. Ann Pharmacother 27:1448–1451, 1993

BRUISER

A 75-year-old woman with a history of previous major depressive episodes (no treatment for years) was hospitalized on the medical floor following a pulmonary embolus due to formation of a deep venous thrombosis in her right thigh. She was initially treated with intravenous heparin and then transitioned to warfarin (Coumadin), 5 mg/day (international normalized ratio [INR], 2.4). After 3 weeks in the hospital, she experienced a recurrence of her major depressive disorder. Her internist prescribed fluvoxamine (Lu- vox), titrating the medication upward to a dosage of 100 mg/day. After 1 week of taking this dosage of fluvoxamine, the patient accidentally, but lightly, bumped her arm on the side rail of her hospital bed. She was sur- prised that she immediately developed a large and ugly bruise on her arm as a result. She informed her internist about this, and he ordered a stat pro- thrombin time, which revealed an INR of 5.8. The fluvoxamine was imme- diately discontinued, but her INR did not fall below 3.0 for another 10 days.

Discussion

This is an example of an inhibitor added to a substrate.

Warfarin’s metabolism is very complex. The more active S-warfarin iso- mer is metabolized primarily by P450 2C9 (Heimark et al. 1987; Linder and Valdes 1999). The less active R-warfarin isomer is metabolized primarily at 1A2 (Lehmann 2000). Fluvoxamine is a strong inhibitor of 1A2, 2C9, and 2C19 and a moderate inhibitor of 3A4 (Christensen et al. 2002; Niemi et al. 2001; von Moltke et al. 1995). The addition of fluvoxamine led to an in- crease in the INR through several mechanisms. First, fluvoxamine signifi- cantly impaired the ability of 2C9 to metabolize the S-warfarin, leading to an increase in the blood level of this warfarin isomer, even though the dosage of warfarin had remained constant throughout (Yap and Low 1999). Second, fluvoxamine’s inhibition of 1A2 and 3A4 yielded an increase in R-warfarin. Although it is a less potent anticoagulant than S-warfarin, R-warfarin does produce some direct anticoagulant effect. Third, R-warfarin is itself an in- hibitor of P450 2C9 (Kunze et al. 1991). Thus, an increase in R-warfarin lev- els led to more inhibition of the metabolism of S-warfarin, yielding higher

S-warfarin levels. These combined influences caused a significant increase

in the patient’s INR, to almost 2½ times the baseline value, which placed the patient in a pathologically hypocoagulable state in which she bruised very easily and was in danger of vascular hemorrhage. The internist eventually had to administer vitamin K to address her persistently high INR.

References

Christensen M, Tybring G, Mihara K, et al: Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 71:141–152, 2002

Heimark LD, Gibaldi M, Trager WF, et al: The mechanism of the warfarin– rifampin drug interaction. Clin Pharmacol Ther 42:388–394, 1987

Kunze KL, Eddy AC, Gibaldi M, et al: Metabolic enantiomeric interactions: the inhi- bition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. Chirality 3:24–29, 1991

Lehmann DE: Enzymatic shunting: resolving the acetaminophen-warfarin contro- versy. Pharmacotherapy 20:1464–1468, 2000

Linder MW, Valdes R Jr: Pharmacogenetics in the practice of laboratory medicine. Mol Diagn 4:365–379, 1999

Niemi M, Backman JT, Neuvonen M, et al: Effects of fluconazole and fluvoxamine on the pharmacokinetics and pharmacodynamics of glimepiride. Clin Pharma- col Ther 69:194–200, 2001

von Moltke LL, Greenblatt DJ, Court MH, et al: Inhibition of alprazolam and de- sipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psycho- pharmacol 15:125–131, 1995

Yap KB, Low ST: Interaction of fluvoxamine with warfarin in an elderly woman. Singapore Med J 40:480–482, 1999