1521-009X/42/3/481$25.00 http://dx.doi.org/10.1124/dmd.113.056721 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 42:481, March 2014 Copyright ª 2014 by The American Society for Pharmacology and Experimental Therapeutics Letter to the Editor Lack of In Vitro–In Vivo Correlation of Adulthood Cytochrome P450 Activities in Low-Birth-Weight Rats Received December 22, 2013; accepted December 26, 2013 Dear Editor, With great enthusiasm we read a report of long-term programming of cytochrome P450 enzyme activities into adulthood as a result of early life insult (Sohi et al., 2013). It is likely that birth weight, a surrogate for early life environment, coupled with postnatal growth could explain part of the variability in CYP enzyme activities. Greater understanding of inter- individual variability in CYP activities would further enable optimization of pharmacotherapies. Although the article covered a comprehensive analysis of select CYP enzymes, we were surprised at the statement that there are no prior studies evaluating the effects of low birth weight in preclinical species or humans. We would like to bring to the authors’ attention published studies that have evaluated the programming effects of maternal low-protein diet on adulthood CYP enzyme status. First, Cherala et al. (2007) examined the effects of two different compositions of low-protein diets administered to pregnant and lactating rat dams on the activities of the five most relevant hepatic CYP isozymes and CYP reductase in adult offspring. The findings of the study by Sohi et al. corroborate the V max data reported by Cherala et al. and further characterize intrinsic clearance. Interestingly, Sohi et al. speculate that the elevated intrinsic clearance could translate into higher clearance of drugs metabolized by the select CYP isozymes examined in this study. However, Cherala et al. (2007) showed that the rate of metabolism of hexobarbital, a drug predominantly metabolized by CYP2C11 and CYP2C12 in male and female rats, respectively, is unaltered in rat offspring. Second, in a recent report, in vivo clearance of midazolam (a CYP3A marker) was lower in both extremes of birth weight, although only women were examined (Cherala et al., 2013). Together, these studies suggest that the in vitro intrinsic clearance data do not correlate with in vivo clearance. As Sohi et al. point out in their discussion, other pharmacokinetic processes such as protein binding and transporters might be confounding in vitro–in vivo correlation. Preliminary data from our research group are supportive of confounding factors (Dubois et al., 2013). We could not agree more with the authors that there is a need for prospective studies to elucidate the effects of perinatal environment on pharmacokinetics during adulthood. Authorship Contributions Wrote or contributed to the writing of the manuscript: Cherala, Pearson, Dubois, Mahmood. Department of Pharmacy Practice, College of Pharmacy, Oregon State University/Oregon Health and Science University (G.C., J.P., B.D., T.M.), Department of Obstetrics and Gynecology, Oregon Health and Science University (G.C.), Portland, Oregon GANESH CHERALA JACOB PEARSON BARENT DUBOIS TAHIR MAHMOOD References Cherala G, Shapiro BH, and D’mello AP (2007) Effect of perinatal low protein diets on the ontogeny of select hepatic cytochrome p450 enzymes and cytochrome p450 reductase in the rat. Drug Metab Dispos 35:1057–1063. Cherala G, Thornburg K, and Edelman A (2013) Birthweight and cytochrome P4503A4/5 activity in obese women. Br J Clin Pharmacol 75:275–276. Dubois BN, Pearson J, Mahmood T, Nguyen D, Thornburg K, and Cherala G (2013) Intrauterine growth restriction decreases diuretic response of furosemide in rats during adulthood (Ab- stract). J Dev Orig Health Dis 4(Suppl 2):S335. Sohi G, Barry EJ, Velenosi TJ, Urquhart BL, and Hardy DB (2013) Protein restoration in low- birth-weight rat offspring derived from maternal low-protein diet leads to elevated hepatic CYP3A and CYP2C11 activity in adulthood. Drug Metab Dispos 42:221–228. Address correspondence to: Dr. Ganesh Cherala, 3303 SW Bond Ave, CH12C, Portland, OR 97239. E-mail: cheralag@ohsu.edu dx.doi.org/ 10.1124/dmd.113.056721. 481 at ASPET Journals on July 6, 2017 dmd.aspetjournals.org Downloaded from