Rhys Whomsley

Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations

In children, the therapeutic benefits and potential risks associated with drug treatment may be different from those in adults and will depend on the exposure, receptor sensitivity and relationship between effect and exposure. In this paper, key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the paediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, secretion and activity of bile and pancreatic fluid, bacterial colonisation and transporters, such as P-glycoprotein (P-gp), are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the paediatric population and adults are organ size, membrane permeability, plasma protein concentration and characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and transporters such as P-gp, which is present not only in the gut, but also in liver, kidney, brain and other tissues. As far as drug metabolism is concerned, important differences have been found in the paediatric population compared with adults both for phase I enzymes (oxidative [e.g., cytochrome P450 (CYP)1A2, and CYP3A7 versus -3A4], reductive and hydrolytic enzymes) and phase II enzymes (e.g., N-methyltransferases and glucuronosyltransferases). Generally, the major enzyme differences observed in comparison with the adult age are in newborn infants, although for some enzymes (e.g., glucuronosyltransferases and other phase II enzymes) important differences still exist between infants and toddlers and adults. Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the paediatric population compared with adults are glomerular filtration and tubular secretion. The ranking of the key factors varies according to the chemical structure and physicochemical properties of the drug examined, as well as to the characteristics of its formulation. It would be important to generate additional information on the developmental aspects of renal P-gp and of other renal transporters, as has been done and is still being done with the different -isozymes involved in drug metabolism.

Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics

Although the majority of oxidative metabolic reactions are mediated by the CYP superfamily of enzymes, non-CYP-mediated oxidative reactions can play an important role in the metabolism of xenobiotics. The (major) oxidative enzymes, other than CYPs, involved in the metabolism of drugs and other xenobiotics are: the flavin-containing monooxygenases, the molybdenum hydroxylases (aldehyde oxidase and xanthine oxidase), the prostaglandin H synthase, the lipoxygenases, the amine oxidases (monoamine, polyamine, diamine and semicarbazide-sensitive amine oxidases) and the alcohol and aldehyde dehydrogenases. In a similar manner to CYPs, these oxidative enzymes can also produce therapeutically active metabolites and reactive/toxic metabolites, modulate the efficacy of therapeutically active drugs or contribute to detoxification. Many of them have been shown to be important in endobiotic metabolism, and, consequently, interactions between drugs and endogenous compounds might occur when they are involved in drug metabolism. In general, most non-CYP oxidative enzymes appear to be noninducible or much less inducible than the CYP system, although some of them may be as inducible as some CYPs. Some of these oxidative enzymes exhibit polymorphic expression, as do some CYPs. It is possible that the contribution of non-CYP oxidative enzymes to the overall metabolism of xenobiotics is underestimated, as most investigations of drug metabolism in discovery and lead optimisation are performed using in vitro test systems optimised for CYP activity.

Amine oxidases and monooxygenases in the in vivo metabolism of xenobiotic amines in humans: has the involvement of amine oxidases been neglected?

In this review, the major enzyme systems involved in vivo in the oxidative metabolism of xenobiotic amines in humans are discussed, i.e. the monooxygenases [cytochrome P450 system (CYPs) and flavin‐containing monooxygenases (FMOs)] and the amine oxidases (AOs). Concerning the metabolism of xenobiotic amines (drugs in particular) by monoamine oxidases (MAOs), this aspect has been largely neglected in the past. An exception is the extensive investigation carried out on the inhibition of the metabolism of tyramine, when tyramine‐containing food is ingested by subjects taking inhibitors of MAO A or of both MAO A and B. Moreover, investigations in humans on the metabolism of drug amines on the market by AOs, such as semicarbazide‐sensitive amine oxidases (SSAOs) and polyamine oxidases (PAOs), are practically nonexistent, with the exception of amlodipine. In contrast to MAOs, monooxygenases (CYP isoenzymes more than FMOs) have been extensively investigated concerning their involvement in the metabolism of xenobiotics. It is possible that the contribution of AOs to the overall metabolism of xenobiotic amines in humans is underestimated or erroneously estimated, as most investigations of drug metabolism are performed using in vitro test systems optimized for CYP activity, such as liver microsomes, and most investigations of drug metabolism in vivo in humans carry out only the identification of the final, stable metabolites. However, for some drugs on the market, the involvement of MAOs in their in vivo metabolism in humans has been demonstrated recently, among these drugs citalopram, sertraline and the triptans are examples that can be mentioned.

Stereoselective renal tubular secretion of levocetirizine and dextrocetirizine, the two enantiomers of the H1‐antihistamine cetirizine

Competition for uptake and/or efflux transporters can be responsible for drug interactions. Cetirizine is mainly eliminated unchanged in urine through both glomerular filtration and tubular secretion. The aim of this study was to investigate whether the eutomer, levocetirizine, and the distomer, dextrocetirizine, have a similar tubular secretion. The renal clearance associated with tubular secretion was calculated from the renal clearance of levocetirizine and dextrocetirizine obtained in a study in healthy volunteers. The values of the unbound fraction in plasma were obtained in an in vitro study of the binding of 14C‐cetirizine and 14C‐levocetirizine to human plasma proteins using equilibrium dialysis and chiral high‐performance liquid chromatography (HPLC) with on‐line liquid scintillation counting. The unbound fraction was 0.074 for levocetirizine and 0.141 for dextrocetirizine. The tubular secretion of dextrocetirizine (44.5 mL/min) is higher than that of levocetirizine (23.1 mL/min), which may have consequences for drug interactions at the renal level. The higher tubular secretion for dextrocetirizine may be due to the higher free fraction available for secretion or to a higher affinity for (a) renal transporter(s) mediating the secretion pathway.

Comment on severe arrhythmia as a result of the interaction of cetirizine and pilsicainide in a patient with renal insufficiency.

o the Editor: In a recent article Tsuruoka et al reported a severe arhythmia as a result of the interaction between cetirizine (20 g) and pilsicainide in a 72-year-old woman with renal nsufficiency. A pharmacokinetic interaction study was subequently performed in vitro and in healthy volunteers. The uthors attempted to explain the interaction as a consequence f competition for excretion via renal P-glycoprotein (P-gp) nd organic cation transporter 2. However, because of limiations in the study design, errors in calculations and units, nd disagreement with published data, we do not believe that he authors are justified in arriving at these conclusions. There are errors in the units for urinary drug excretion for oth drugs (nanograms instead of micrograms); otherwise, he excretion data are approximately one one thousandth of hose published. The values presented for renal clearance of ilsicainide and cetirizine do not correspond with the values btained by calculating these parameter values according to he formula provided (187 and 56.5 mL/min, respectively, rom the mean values of amount excreted in urine/area under he curve). The latter values are similar to published values or pilsicainide (196.8 mL/min) and cetirizine (36 mL/min) n Japanese subjects. The value for half-life (t1⁄2) (estimated from elimination rate onstant) for cetirizine in the presence of pilsicainide (16 ours) is similar to the value in patients requiring dialysis 19 hours), even though the renal clearance of cetirizine is till similar (33.5 mL/min) to that previously observed in ormal Japanese subjects. The sampling intervals (2-12 ours) do not allow an accurate estimation of t1⁄2, particularly f inhibition of renal excretion is anticipated, because it is idely accepted that sampling for at least 3 t1⁄2 values is ecessary for the reliable determination of t1⁄2 or elimination ate constant. The article states that the “drug-drug interaction of pilsicinide and cetirizine occurred during the elimination phase 6-12 hours] in the kidney.” However, more than 75% of the mount recovered in 12 hours had already been eliminated in he time interval from 0 to 6 hours, and there was no effect on he amount of either drug excreted during this period. Beause the maximum concentration occurred within 2 hours for oth drugs, the maximum effect should have been expected ver 0 to 6 hours.