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Gender Differences in p-Glycoprotein: Drug Toxicity and Response

Harry R. Horvitz Center for Palliative Medicine, Cleveland Clinic, Cleveland, OH

To the Editor:

The review of chemotherapy for small cell carcinoma by Dr. Singh et al found that women experienced more myelosuppression, nausea, vomiting, and stomatitis than men.¹ Survival was also better in women. Drug therapy consisted of combinations of cyclophosphamide, vincristine, doxorubicin, etoposide, and platin. The authors suggested that sex differences in toxicity and response might be related to reduced etoposide or doxorubicin clearance, differences in body mass index or composition, or differences in drug pharmacodynamics.¹

Cyclophosphamide, doxorubicin, etoposide, and vincristine are metabolized by the CYP3A4.² Cyclophosphamide, vincristine, and doxorubicin are also inhibitors of CYP3A4.² The drug transporter p-glycoprotein derived from the MDR1A gene shares common substrates with CYP3A4. In particular, vincristine, doxorubicin, and etoposide are also subject to p-glycoprotein cellular extrusion.^3,4,5,6 Drug transporters, particularly p-glycoprotein, influence bioavailability drug distribution, intracellular drug concentrations, drug metabolism, and elimination.⁷ Drug metabolism through CYP3A4 alone does not adequately explain the observed interindividual variability in drug distribution or response. Transport and metabolism must be considered together.⁸

p-glycoprotein and CYP3A4 act in concert to reduce absorption of xenobiotics along the gastrointestinal tract and increase drug elimination from the liver. The repeated extrusion and subsequent reabsorption of drug along the gastrointestinal tract increases drug metabolism by repeated exposure to CYP3A4 and as a result reduces drug bioavailability.⁵ In addition, p-glycoprotein increases fecal elimination by extruding drug into bile.

Genetic deficiencies in p-glycoprotein reduce drug excretion into bile and increase drug half-life of p-glycoprotein–dependent drugs.⁹

Intracellular levels of p-glycoprotein substrate drugs are increased when p-glycoprotein is blocked or genetically reduced.^5,6,10,11 This results in increased drug exposure to CYP3A4 and metabolism, but also drug interactions, and reduced drug elimination. Reduced p-glycoprotein predisposes to greater competitive intracellular drug interactions for CYP3A4.⁶

CYP3A4 in humans is generally the same in females and males, but hepatic p-glycoprotein is 2.4-fold lower in females (though there are wide individual differences in CYP3A4 and p-glycoprotein levels).^6,12 Reduction in p-glycoprotein in females relative to males will reduce vinca alkaloids, doxorubicin, etoposide, and docetaxel elimination and prolong drug half-life. Reduction in glycoprotein will lead to accumulate of these glycoprotein substrate drugs in brain, heart, liver, and gastrointestinal tract.^10,11,13,14 The end result is a greater risk for myelosuppression and gastrointestinal toxicity in females and prolonged drug elimination.

In summary, sex differences in p-glycoprotein will influence intracellular levels of p-glycoprotein substrate drugs; increase competitive drug interactions and delay drug elimination.¹⁵ As a result, females will experience greater drug toxicity with p-glycoprotein substrate drugs, but also have better responses due to prolonged drug exposure. This may explain, in part, the findings of Singh et al.

Author's Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Singh S, Parulekar W, Murray N, et al: Influence of sex on toxicity and treatment outcome in small-cell lung cancer. J Clin Oncol 23:850-856, 2005[Abstract/Free Full Text]

2. Baumhakel M, Kasel D, Roa-Schymanski RA, et al: Screening for inhibitory effects of antineoplastic agents on CYP3A4 in human microsomes. Int J Clin Pharmacol Ther 39:517-528, 2001[Medline]

3. Toffoli G, Corona G, Basso B, Boiocchi M: Pharmacokinetic optimization of treatment with oral etoposide. Clin Pharmacokint 43:441-66, 2004[CrossRef]

4. Stephens RH, O'Neill CA, Bennett J, et al: Resolution of P-glycoprotein and non p-glycoprotein effects on drug permeability using intestinal tissues from MDR lA (–/–) mice. Br J Pharmacol 135:2038-2046, 2002[CrossRef][Medline]

5. Benet LZ, Cummins CL: The drug efflux: Metabolism alliance—Biochemical aspects. Adv Drug Deliv Rev 50:S3-S11, 2001

6. Benet LZ, Cummins CL, Wu CY: Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int J Pharm 277:3-9, 2004[CrossRef][Medline]

7. Marzolini C, Paus E, Buclin T, et al: Polymorphisms in human MDR1 (P-glycoprotein): Recent advances and clinical relevance. Clin Pharmacol Ther 75:13-33, 2004[CrossRef][Medline]

8. Kim RB: Transporters and xenobiotic disposition. Toxicology 181-182:291-297, 2002

9. van Asperen J, Schinkel AH, Beijnen JH, et al: Altered pharmacokinetics of vinblastine in MDR lA P-glycoprotein deficient mice. J Natl Cancer Inst 88:994-999, 1996[Abstract/Free Full Text]

10. van Asperen J, van Tellingen O, Tijssen F, et al: Increased accumulation of doxorubicin and doxorubicinol in cardiac tissue of mice lacking mdr la P-glycoprotein. Br J Cancer 79:108-113, 1999[CrossRef][Medline]

11. van Asperen J, van Tellingen O, Schinkel AH, et al: Comparative pharmacokinetics of vinblastine after a 96-hour continuous infusion in wild-type mice and mice lacking mdr la P-glycoprotein. J Pharmacol Exp Ther 289:329-333, 1999[Abstract/Free Full Text]

12. Schuetz EG, Furuya KN, Scheutz JD: Interindividual variation in expression of P-Glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275:1011-1018, 1995[Abstract/Free Full Text]

13. Cummins CL, Wu C, Benet LZ: Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 72:474-489, 2002[CrossRef][Medline]

14. Yokogawa K, Takahashi M, Tamai I, et al: P-glycoprotein-dependent disposition kinetics of tacrolimus: Studies in mdr la knockout mice. Pharm Res 16:1213-1218, 1999[CrossRef][Medline]

15. Chiou WL, Chung SM, Wu, Ta C: Potential role of P-Glycoprotein in affecting hepatic metabolism of drugs. Pharm Res 17:903-905, 2000[CrossRef][Medline]

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