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To the Editor: Some studies suggest that drug metabolism by Cytocrome P 3A4 450 (CYP3A4) differs by ethnic group. Nifedipine¹ and midazolam,² drugs considered to be markers of CYP3A4 activity, exhibit reduced clearance and higher bioavailability in Mexican men compared with white men. Sildenafil (Viagra, Pfizer Inc, New York, NY), a popular drug for the treatment of erectile dysfunction, is also biotransformed by CYP3A4.³ Therefore, we studied the pharmacokinetics of oral sildenafil in 24 healthy, young, male Mexican volunteers for 12 hours after a 100-mg dose.

Methods
Plasma concentrations of sildenafil and its main metabolite, desmethyl sildenafil, were determined by a high-performance liquid chromatographic method based on that described by Cooper et al.⁴ Plasma samples were extracted with benzene and analyses were performed using a reversed-phase C18 column eluted with a 0.02-mol/L 30% acetonitrile/70% NaH₂PO₄ buffer (flow rate, 1 mL/min) at room temperature. Spectrophotometric detection was carried out at 230 nm. The method was linear in the ranges of 35 to 1053 ng/mL and 10 to 250 ng/mL for sildenafil and desmethyl sildenafil, respectively. Intraday and interday accuracy ranged from 96% to 114%. Coefficients of variation were always less than 14.9%.

Results
Pharmacokinetic parameters, mean (SEM), for sildenafil were: maximum concentration (C_max)=1044 (95) ng/mL; maximum time (t_max)=1.2 (0.2) hours; area under the curve (AUC)=2960 (160) ng x h/mL; and half-life=4.3 (0.4) hours. Pharmacokinetic parameters for desmethyl sildenafil were: C_max=133 (13) ng/mL; t_max=1.3 (0.2) hours; AUC=523 (52) ng x h/mL; and half-life=4.9 (0.8) hours. Figure 1 shows mean (SEM) plasma sildenafil concentrations observed in the Mexican men after administration of a 100-mg dose. Plasma concentrations reported by the manufacturer³ for white men under similar conditions and using a comparable analytical method⁴ are shown for comparison. Sildenafil concentrations in the Mexican men were about 2 times higher than in white men. Nonetheless, half-life was similar (about 4 hours) in both groups. The desmethyl sildenafil–sildenafil AUC ratio in Mexican men was 19%, whereas that reported for white men is 55%,⁵ suggesting a lower metabolism rate in Mexican men.

View larger version (14K): [in this window] [in a new window] Figure. Mean Plasma Sildenafil Concentrations Solid circles indicate sildenafil concentrations observed in 24 healthy Mexican men after oral administration of a single 100-mg dose; open circles, plasma concentrations reported by the manufacturer3 for healthy white men (shown for comparison); and error bars, SEM.

Comment
Our results provide evidence for increased sildenafil bioavailability in Mexican men compared with white men. Since this drug is mainly eliminated by metabolism by CYP3A4³ and evidence exists for reduced CYP3A4 activity in Mexican men,^1-2 it seems likely that interethnic differences in sildenafil bioavailability result from reduced biotransformation in Mexican men. Since half-life values were similar, increased bioavailability probably results from a reduced first-pass effect rather than decreased systemic clearance.

It should be noted that a strict comparison between Mexican men and white historical controls cannot be performed at present since published information on sildenafil pharmacokinetics in white men is still incomplete. Notwithstanding, our data suggest that oral sildenafil bioavailability in Mexican men is increased. This also may be the case for South Asian and Nigerian individuals, who also exhibit reduced CYP3A4 activity.⁶ Therefore, pharmacokinetic studies should be performed in these ethnic groups to rationally establish sildenafil dosing and to presumably optimize sildenafil efficacy and safety for each population.

Francisco J. Flores-Murrieta, PhD; Gilberto Castañeda-Hernández, PhD; Vinicio Granados-Soto, PhD; Jorge E. Herrera, MD, PhD
Centro de Investigación y de Estudios Avanzados and Escuela
Superior de Medicina Instituto Politécnico Nacional
México City, México

1. Castañeda-Hernández G, Palma-Aguirre JA, Montoya-Cabrera MA, Flores-Murrieta FJ. Interethnic variability in nifedipine disposition: reduced systemic plasma clearance in Mexican subjects. Br J Clin Pharmacol. 1996;41:433-434. WEB OF SCIENCE | PUBMED 2. Chávez-Teyes L, Castañeda-Hernández G, Flores-Murrieta FJ. Pharmacokinetics of midazolam in Mexicans: evidence for interethnic variability. Clin Drug Invest. 1999;17:233-239. FULL TEXT 3. Viagra (sildenafil citrate) [product monograph]. New York, NY: Pfizer Inc; August 9, 1999. Available at: http://www.viagra.com. 4. Cooper JDH, Muirhead DC, Taylor JE, Baker PR. Development of an assay for the simultaneous determination of sildenafil (Viagra) and its metabolite (UK-103,320) using automated sequential trace enrichment of dialysates and high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl. 1997;701:87-95. FULL TEXT | PUBMED 5. Walker DK, Ackland MJ, James GC, et al. Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog, and man. Xenobiotica. 1999;29:297-310. FULL TEXT | WEB OF SCIENCE | PUBMED 6. Sowunmi A, Rashid TJ, Akinyinka OO, Renwick AG. Ethnic differences in nifedipine kinetics: comparisons between Nigerians, Caucasians, and South Asians. Br J Clin Pharmacol. 1995;40:489-493. WEB OF SCIENCE | PUBMED

Letters Section Editors: Phil B. Fontanarosa, MD, Deputy Editor; Stephen J. Lurie, MD, PhD, Fishbein Fellow.

JAMA. 2000;283:1825-1826.

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