Table 2.

Summary pharmacokinetic and pharmacogenetic studies of relevant membrane transporter substrates

Drug	Relevant transporters involved in transport of drug	PK and PGx results in children
Digoxin	ABCB1	Higher bodyweight-corrected digoxin clearance in term neonates and young children [36–38]. Renal clearance of digoxin in young children may be more dependent on ABCB1-mediated tubular secretion than in adults [39]
Tacrolimus	ABCB1	PGx studies of ABCB1 in relation to tacrolimus PKs appear contradictory [42, 43, 46, 47]. In pediatric liver transplant recipients, high intestinal ABCB1 mRNA expression was associated with a twofold higher tacrolimus clearance [48]
Daptomycin	ABCB1	Higher body size-corrected renal daptomycin clearance in neonates and younger infants [51–53]
Fexofenadine	OATP2B1, ABCB1, MRP2	Apparent bodyweight-corrected oral clearance was 1.5-fold lower in children 6 months to 6 years than in children 6–12 years [58]
Morphine	OCT1, ABCB1, ABCC2, ABCC3, OATP1B1	Neonates and infants have low morphine clearance in the first 10 days of life, increasing thereafter, largely due to immature UGT2B7 metabolism, but transporters may contribute [64, 65]. Neonates are more prone to morphine-related respiratory depression [66]. ABCB1 genotype was associated with respiratory depression in older children, in contrast to an adult study [62]. Also, ABCB1 genotype affects the M3G-formation and OCT1 genotype is associated with variation in morphine clearance and glucuronide-metabolites formation [68]
Pravastatin	OATP1B1, OATP2B1, OATP1B3, ABCB1, ABCC2	Children with hypercholesterolemia and the SLCO1B1 –11187GA variant had lower mean pravastatin AUCs than those with the wild-type, in contrast to an adult study where the opposite effect was found [71, 72]. No age-related variability in pravastatin PKs from children aged 5 years onwards [73]
Atorvastatin	OATP1B1, BCRP	Atorvastatin PKs in older children similar to adult PKs [74]
Bosentan	OATP1B1, OATP1B3, OATP2B1	In children, an exposure limit was found at a much lower dose than in adults, which might be due to intestinal OATP2B1 saturation [80]
Ondansetron	OCT1	Ondansetron PKs and clinical efficacy have been correlated with OCT1 genotypes in adults [82]. Ondansetron clearance increased with age in children aged 1–48 months [83]
Metformin	OCT, MATE1, MATE2 K	Metformin PKs in children from 9 years of age onwards were comparable with adult PKs, suggesting stable OCT and MATE activity [91]
Cimetidine	OCT2, MATE1, MATE2 K, OAT2	In neonates and children, cimetidine (and metabolites) renal clearance accounts for 80–90 % of total clearance, whereas in adults it accounts for 60 % of total clearance [93–95]. The relatively high renal clearance suggests mature OCT2 activity at birth in the presence of immature GFR [99]
Tramadol	OCT1	In adults, OCT1 genotype was related to metabolite plasma concentrations and prolonged miosis [101]. Tramadol and metabolite PKs show age-related changes in neonates [102]
Methotrexate	OATP1B1, ABCC2	Increased renal toxicity in children 0–3 months old compared with infants 7–12 months [106]. From 1 year of age onwards, body size-corrected methotrexate clearance decreased linearly with age [107]. SLCO1B1 genotype was associated with increased AUC and was a predictor for toxicity [107]
Mycophenolate mofetil	MRP2	In pediatric patients, ABCC2 rs717620 allele has been associated with reduced exposure to MPA, more adverse effects, and rejection [114]
Acyclovir/valacyclovir	4F2hc, HPT1, OAT1, OAT3	In neonates, the IV acyclovir bodyweight-corrected clearance showed a twofold increase from 25 to 41 weeks of gestational age [118]. In older children, 1 month to 5 years, apparent oral clearance of valacyclovir in children less than 3 months of age was 50 % than that in older children [119]
Adefovir	OAT1, MRP4	Adefovir is partly renally cleared (45 %) [120, 121]. In 45 children (age range 2–17 years) receiving oral adefovir dipivoxil, weight-corrected mean apparent clearance and renal clearance were higher in younger children [122]

ABC adenosine triphosphate (ATP)-binding cassette, AUC area under the plasma concentration–time curve, BCRP breast cancer resistance protein, GFR glomerular filtration rate, HPT human oligopeptide transporter, IV intravenous, M3G morphine-3-glucuronide, MATE multidrug and toxin extrusion protein, MPA mycophenolic acid, mRNA messenger RNA, MRP multidrug resistance-associated protein, OAT organic anion transporter, OATP organic anion-transporting polypeptide, OCT organic cation transporter, PGx pharmacogenetics, PK pharmacokinetic, UGT uridine 5′-diphospho-glucuronosyltransferase