The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 ( CYP2C19 ) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype‐guided pediatric dosing of PPI medications. Children aged 5–17 years old with gastric‐acid‐related conditions were randomized to receive either conventional dosing of a PPI or genotype‐guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype‐guided dosing arm ( P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype‐guided dosing arm. The number of participants who reported an infection was marginally lower in genotype‐guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype‐guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype‐guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI‐associated infections. A future large scale randomized clinical trial of CYP2C19 genotype‐guided pediatric dosing of PPI medications in children is warranted.

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The present investigation sought to characterize the relationship between ontogeny and Na(+)-P(i) transporter expression in the rat kidney. Results showed that the maximal reaction rate (nmol.mg protein-1.10 s-1) of Na(+)-P(i) transport was highest in 21-day-old rats (2.26 +/- 0.26), was lower in 42- to 45-day-old rats (1.44 +/- 0.19) and 4-mo-old rats (0.78 +/- 0.15), and was lowest in 14-day-old rats (0.50 +/- 0.16) (P = 0.0009, n = 3). The Michaelis constants (mM Pi) were not significantly different in the four age groups. Northern blot analysis revealed that the abundance of Na(+)-P(i) transporter mRNA was similar in all four age groups (n = 5). Western blot analysis demonstrated the highest immunoreactive protein signal in the 21-day-old rat (Na(+)-P(i)/beta-actin = 4.15 +/- 1.16), followed by decreasing protein levels in 42-day-old rats (2.13 +/- 0.22), 4-mo-old rats (0.85 +/- 0.25), and 14-day-old rats (0.75 +/- 0.37) (P = 0.022, n = 5). Immunohistochemical analysis of kidney cortex in the four age groups showed specific staining of only apical membranes in all samples. We conclude that posttranscriptional mechanisms play a role in regulating this transporter during rat ontogeny.

Phosphates are necessary for proper skeletal growth and function, as well as for growth and development of cells. Phosphate repletion depends partly on the function of the renal sodium-phosphate (Na+/Pi) transport system that functions to recover filtered urinary phosphate. It has been suggested that in order to meet the higher phosphate requirement of the developing animal, the weanling rat would have a greater adaptive response to chronic phosphate deprivation than the adolescent rat. The current study sought to characterize the adaptive response to dietary phosphate deprivation in terms of Na+/Pi transporter activity, and mRNA and immunoreactive protein levels. Weanling and adolescent rats were pair fed either a low-phosphate diet (LPD) or a control-phosphate diet (CPD) for 1 week. Maximal rates of transport (Vmax) were not different in weanling or adolescent rats on CPD (weanling 2.13 +/- 0.29 nmol/mg protein/10 sec, and adolescent 1.41 +/- 0.036 nmol/mg protein/10 sec, n = 3). K(m) values were not different in either group on CPD (weanling 0.15 +/- 0.08 mM Pi, and adolescent 0.22 +/- 0.13 mM Pi). There were no difference in mRNA abundance (Na+/Pi transporter/1B15 = 0.194 +/- 0.12 for weanling and 0.230 +/- 0.03 for adolescents, n = 3) or immunoreactive protein levels (Na+/Pi transporter/beta-actin = 0.232 +/- 0.01 for weanlings and 0.300 +/- 0.05 for adolescents, n = 3) in the two groups when fed CPD. After chronic Pi deprivation, the weanling rat showed a greater adaptive response than the adolescent as measured by Vmax values (weanling LPD/CPD = 2.01, P < 0.01; adolescent LPD/CPD not different; n = 3), mRNA signal intensity (weanling LPD/CPD = 1.86, P < 0.05; adolescent LPD/CPD not different; n = 3), and protein signal intensity (weanling LPD/CPD = 3.63, P < 0.01, and adolescent LPD/CPD 1.91, P < 0.05; n = 3). K(m) values were not affected by LPD. Immunohistochemical analysis of kidney cortex showed greater apical staining in both groups on LPD, with the increase being noticeably greater in the weanlings. Furthermore, two-way analysis of variance demonstrates a significant adaptive response in the weanling period in regard to maximum transport capacity (Vmax) and immunoreactive protein (Western), suggesting a synergistic effect between the developmental stage and low-phosphate diet. Therefore, it appears that the adaptive response is greater in the more rapidly developing animal (the weanling), and these results suggest a compensatory mechanism to conserve phosphate during periods of rapid growth.

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