There has been a lot of work and research carried out since the discovery that age affects drug metabolism which can lead to toxicity in the 1960s and 1970s. Therefore more knowledge and understanding about how drug metabolism is affected by age is vital, which lead to the finding out of the important role of the liver, cytochrome enzyme family, genetics and transporter systems in drug metabolism. Age was discovered to have remarkable effect on most of this phenomena involved in drug metabolism such as liver volume reduction, decrease in activity of some cytochrome enzymes family. However, the problem of getting healthy liver tissue of human and some restriction ethically have limited the studies of drug metabolism effects on age and toxicity. There are numerous factor that also influence the toxicokinetics of drugs in human. Adult population have more advantage in terms of studies involving drugs metabolism than the older population and paediatric population due to risks involved and ethical reasons in studies on new drugs which discourage testing of drugs in the older and paediatric population. Changes in drug metabolism may be due to differences in toxicokinetics which include absorption, distribution, metabolism or excretion. There are numerous organs and system that decline with age and also underdeveloped organs and systems in infants or paediatrics which affects drug metabolism has result of this conditions. Advancing age results in reduce gastric acid secretion, gastric emptying, gastrointestinal mobility, surface area for absorption, liver size and function, renal function, lean body mass, total water content, serum albumin, cardiac output and increase body fat which affect directly or indirectly drug metabolism and can lead to toxicity.
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Metabolism cause drugs to become more water soluble in order to readily remove them from the body after they have perform their action in the body. This process takes place mainly in the liver cells and produces metabolites which are not active and sometimes non-toxic, although some metabolites may be toxic. There are drugs that their parent drug are in active and the metabolites produced are active. The mechanisms of drug metabolisms are divided into phase 1 and phase ∏. Phase 1 reactions involves structural change of drug molecules and phase ∏ reaction consisting of conjugation with a more water soluble compound. Oxidation, reduction and hydrolysis are main reaction occurring in phase 1 with involvement of cytochrome p450 enzymes and other enzymes in oxidative metabolism mainly. Maturational changes occurs from birth in both phase 1 and phase ∏ metabolic pathways which is usually not fully mature at birth.
The liver is most important organ for drug metabolism quatitatively and forms about 6% of the body mass at birth but around 3% of the body mass in the adult. Growth is associated with reduction in blood flowing into the liver and liver volume consequently resulting in reduced metabolic clearance with drugs that require high hepatic removal whereas drugs with low hepatic removal are usually less removed which can lead to toxicity. Depending on the enzyme system involved, there can be production of low or high plasma concentration of active principle due to different capacities to metabolize drug in the paediatric or older people than in adult. There are curative agent in children that produces metabolites whereas this metabolites are not present normally in adult and the metabolites may be the cause of efficacy and/or toxicity seen with administration of drug in children for example children receiving theophylline produces caffeine and other examples of curative agent that differ in metabolite production are paracetamol, salicylamide, chloramphenicol, valproic acid and cimetidine. There is also different in level of expression of metabolites in children compared to adult although they express the same enzyme complement but there is no knowledge of example of metabolite production not normally present in adult that are seen in the older population. Few expections occurs though in most cases because differences between the children and adults are in ratio of metabolite compared to the parent drug rather than metabolites that unequally specific to the paediatric.
PHASE 1 REACTIONS
CYTOCHROME P450 (CYP) SYSTEM
The oxidative metabolism of many drugs and chemicals are catalyze by cytochrome p450 isoenzyme superfamily that consist of over fifty proteins. The enzymes are present in the smooth endoplasmic reticulum of the liver and other tissue in their lipophilic membrane which can be isolated and they become vesicles called microsomes. Different cytochrome p450 family are responsible for different metabolism for example cytochrome p450 families 1-4 are responsible for foreign compounds metabolism while the other cytochrome p450 families are responsible for endogenous substrates metabolism. The metabolic activation of many chemical carcinogens and toxins with phase 1 metabolism of most drugs used clinically are also the responsibility of cytochrome p450.
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There are two isoforms of CYP1A subfamily namely CYP1A1 AND CPY1A2. CYP1A1 are mainly extra-hepatic. CYP1A2 is concerned mainly with the metabolism of paracetamol, caffeine, theophylline, imipramine, aromatic amines, warfarin and phenacetin. All demethylations of N-1, N-3, N-7 and ring hydroxylation of C-8 in the metabolism of caffeine and theophylline are also the responsibility of CYP1A2 and other CYP isozymes like CYP3A4/5, CYP2A6 and CYP2E1. In paediatric, CYP1A2 is not usually detectable until one to three months infant age and it's increases until about three years but remains the same with adults afterwards. Demethylation of caffeine N-3 depends on CYP1A2 in neonates, infants and adults but N-3 demethylation is more important in young infants. Caffeine metabolic pathway matures with postnatal age especially with total demethylation, demethylation of N-7 and N-3 demethylation whereas demethylation of N-1 show no variation but maturation occurs at one and half years of age. Hydroxylation of C-8 is usually developed at one month in few infants than in adults. The activity of most demethylation was found to be lower in neonates and infants than adult and diet of infants also affect development of CYP1A2 activity. There is decrease in activity of CYP1A2 in elderly with caffeine. Most of this variation leads to toxicity and it's dose dependent too.
There are three isoforms of this subfamily namely CYP2A6,2A7 and 2A13. CYP2A6 is mainly involved in catalysis of coumarin 7-hydroxylation. Urinary excretion of 7-hydroxycoumarin is almost the same in children of six to fourteen years and adults but the rate of elimination is unchanged or reduced for CYP2A substrates in the elderly which can cause toxicity in relation to dose given.
The isoforms of this subfamily are CYP2C9, CYP2C19 and CYP2C8. They are involved in metabolism of various therapeutic agent for example anti-inflammatory drugs(non-steroidal), anticonvulsants, warfarin, propranolol, diazepam etc and might contribute to metabolism of endogenous agents e.g arachidonic acid. CYP2C isozymes is detectable early in neonatal period, one month level is usually about one-third of adults and remains the same until about one year of age. From birth there is interindividual variation in CYP2C9 protein and activity until about 18years with 36 fold till five months and less variation between five months and eighteen years. Phenytoin(anticonvulsant) and substrate of CYP2C9 pharmacokinetics is affected which can lead to toxicity. Expression of CYP2C19 increases from birth for about five month and variation of individual between five months and ten years is about 22 fold but from ten years there is similarity in activity and expression with adult. In the elderly there is decrease in the rate of elimination of substrates of both CYP2C19 and CYP2C9 probably causing toxicity depending on dose.
CYP2D6 is involved in the metabolism of drugs like β-blockers, anti arrhythmic drugs, antidepressants (tricyclic and non-tricyclic), codeine, captopril, ondansetron etc. There is increase in the protein expression of CYP2D6 from few weeks postnatal age to about five years and reaches about two- third of the adult level. There is also CYP2D6 polymorphism in children but there is unchanged rate of elimination of substrates of CYP2D6 in the elderly. Most of this alteration with age can affect the metabolism leading to toxicity and it's dose dependent.
CYP2E1 contribute to the metabolism of small molecules like paracetamol, aniline, ethanol, N-nitrosodimethylamine. The enzymes rises after birth till about one year become about 40% of adult level but reaches 100% adult level between one year and ten year. It decrease or remain unchanged with age using substrates like paracetamol and chloroxazone but recent study shows that there is increase in CYP2E1 activity with age in men than in women resulting in toxicity depending on dose.
CYP3A isoforms are CYP3A4, CYP3A5, CYP3A7; they are the major CYP isoforms found in the liver and small intestine. They are also involved in oxidation of numerous substrates.CYP3A5 is independent of age and variably high in expression. CYP3A4 is majorly expressed in adult liver while CYP3A7 is majorly expressed in foetal liver. The isoforms are closely related structurally but differs in monooxygenase reaction capacity function. CYP3A7 in foetal liver is very active until after first week of birth and starts to decrease till it is absent in adult liver. CYP3A4 is very weak or not present in foetus but rises after birth and it is responsible for biotransformation of cisapride( serotonin 5-HT4 agonist) which can cause cardiac toxicity in neonates due to steady increase in activity of CYP3A4 in metabolism of cisapride that exceeds adults value activity especially in neonates and adult that don't carry risk factor affecting them. Another CYP3A4 substrate, intravenous midazolam(sedative) metabolism is lower in neonates than in infants greater than 3months of age but as a result of low activity of CYP3A4 in the intestine of adult there is increase in bioavailability of midazolam following oral ingestion in preterm infants compared to adults. CYP3A4 development is fastened with diet in infants. In the elderly there is inconclusive information about the activity and expression of CYP3A but it remain unchanged or decrease with age.
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FLAVIN-CONTAINING MONOOXYGENASES (FMOs)
Flavin- containing monooxygenases are vital in oxidative of various foreign compounds containing nucleophilic nitrogen, phosphorus-heteroatoms, selenium, sulfur that are NADPH dependent. There are six member gene family of the enzyme (FMO 1-6). In the paediatric, FMO1 expression was highest from 2months to 4months gestation and a mechanism coupled with conception suppressed completely expression of FMO1 within three days post natal. FMO3 expression was not present during neonatal period but low level was present between 2months and 4months gestation; from one to two years of age FMO3 expression was present and increase till about eleven years but from eleven years to eighteen years, there is gender -interdependence in the increase of FMO3 expression. There is a hepatic null FMO phenotype in neonate due quick post natal suppression of FMO1 and FMO3 expression delayed onset.
MONOAMINE OXIDASES (MAOs)
Monoamine oxidases are involved in the exogenous and endogenous compounds metabolism and found in the mitochondria of liver, kidney, lungs, brain, intestine and platelets. Their concentration is low in liver and higher in other tissues. The two monoamine oxidases that take part in drug metabolism are MAO A and MAO B. During conception MAO A activity is very high and reduces quickly in the first two year of age and becomes steady afterwards. MAO B activity is low at conception, steady in early age and increases with increase in age.
ALCOHOL DEHYDROGENASE (ADH)
Alcohol dehydrogenases are cytosolic isozymes that are involved in the reversible oxidation of alcohols to aldehydes and metabolism of endogenous compounds like steroids and retinol. For example hydroxyzine to cetirizine. There are six classes of alcohol dehydrogenase ADH 1-6, five of the ADH 1-5 are found in man. In neonates, there is immature development of the activity of ADH but from one to two and half year of age, the activity of ADH is the same or greater than in adult. There is no much difference in the activity of ADH in adult compared to the elderly.
MOLYBDENUM HYDROXYLASES (ALDEHYDE OXIDASE AND XANTHINE OXIDASE)
Aldehyde oxidase(AO) and Xanthine oxidase(XO) are involved in exogenous and endogenous substrates biotransformation. XO is involved in oxidative hydroxylation of hypoxanthine to xanthine, xanthine to uric acid and purine metabolism last two steps in mammals. AO and XO are similar structurally but AO takes part in metabolism of tamoxifen, ziprasidone, zaleplon, famciclovir, zonisamide etc. XO activity in plasma is very high in babies compared to adult and AO activity is immature until about 12months after. XO activity is independent of age in elderly.
NADPH-CYTOCHROME P450 REDUCTASE
The electron giving partner to CYP enzymes are flavin adenine dinucleotide(FAD) and flavin mononucleotide(FMN) contained in the cytochrome p450 reductase. NADPH reducing enzymes are passed to the FAD of cytochrome p450 reductase and then to CYP enzymes via the FMN of the cytochrome p450 reductase. There is no much significant change with age with NADPH-cytochrome p450 reductase.
Aldo ketoreductases are present in erythrocytes, liver and are cytosolic enzymes involved in reduction of carbonyl groups. They also metabolized hypolipidemic drugs(fenofibrate) and anti cancer drugs(anthracyclines). Prostaglandin E1(PGE1) are metabolized by ketoreductase . ketogroup reduction often produce active metabolism which can cause toxicity with age for example idarubicin produces idarubicinol (alcohol product) and PGE1 produces 13,14-dihydro-15- ketoprostaglandin E1 which is further reduce to active compound 13, 14-dihydro-prostaglandin E1.
There is decrease in the activity of esterases in newborn than in adult but in the elderly physical weakness reduces the activity of esterases especially those with trauma, undergoing surgery, injured or ill. From 7months gestation to 12months of age, there is quick increase in the activity of plasma arylesterase and pseudocholinesterase activity ,but no significant alteration occurs afterwards. There is abrupt increase in erythrocyte acetylcholinesterase activity between conception and 12months i.e erythrocytes are not matured before conception. Ester forms of drugs are mostly incompletely hydrolyzed in neonates due to low serum concentration that result e.g erythromycin estolate, chloramphenicol palmitate
PHASE ∏ REACTIONS
Conjugation with acetyl group by drugs like isoniazid, p-aminosalicylic, p-aminobenzoic acid, sulfamethazine and toxic agent is control by activity of N-acetyltransferase(NAT). in premature and newborns, there is acetylation of p-aminobenzoic acid by N-acetyltransferase1(NAT1) which increase slightly in infants and is reduced in children. N-acetyltransferase2(NAT2) involved in caffeine and isoniazid metabolism shows that in infants there are slow acetylators or fast acetylators that are not matured with caffeine and with isoniazid acetylation maturation occurs after one year, as fast acetylors increases with age till four years peak.
Conjugation of methyl group are the responsibility of S-methytransferase, O-methyltransferase, and N-methyltransferase which are involved in transfer of methyl group to oxygen-nucleophile, nitrogen-nucleophile and sulfur nucleophile.
Theophylline N-7-methylation in newborn to caffeine is well matured but oxidative demethylation is insufficient and matures after several months of age.
Thiopurine-s-methyltransferase(TPMT) is involved in the metabolism of azathiopurine (converted to 6-MP) and catalyzes thiopurines metabolism e.g 6-MP(antiblastic drug). TPMT is a cytosolic polymorphic enzyme which is gene specific and are present in many tissue and erythrocyte. In paediatric, there is high activity of TPMT in about 90%, about 8% have intermediate activity and 0.3% have low activity. Inactivation by TPMT which affects the efficacy of 6MP in individual with low TPMT activity experience severe toxicity with 6MP standard doses.
There are various UDP glucoronsyltransferase(UGT) isozymes present in human. Glucuronidation in paediatric reaches adult level when they are 12weeks to24weeks old, 12months, 36months or later in age depending on the drug. At 12weeks of age, bilirubin glucuronidation which is the responsibility of UGT1A1 isozymes approach adult level but occurs at very low levels in neonates liver. For example chloramphenicol with lower glucuronidation in paediatric can lead to toxicity because glucuronidation is clearly insufficient in most premature babies and mature babies. Therefore high concentration of unmetabolized chloramphenicol may increase in amount leading to serious toxicity which cause circulating collapse or grey baby syndrome with standard dose per bodyweight. These prompt the more studies and the dose was regulated on weight, gestation and postnatal age basis. UGT2B7 also metabolize chloramphenicol and some UGT isoforms are also eliminates it. 3-glucuronides(M3G) and 6-glucuronides(M6G) are formed as a result of UGT2B7 metabolizing morphine. There is increase in the quality of morphine glucuronidation activity after neonate age. For example there is increase in epirubicin glucuronidation activity with age and elimination of epirubicin (malignant disease treatment)is majorly by UGT2B7 glucuronidation. In children of 7 to 10 year, there is insufficient glucuronidation of paracetamol and salicylamide in correlation with adults. UGT1A6 is the main glucuronidation isozymes of paracetamol although UGT1A1 and UGT1A9 also takes part in the glucuronidation. It was observed that UGT1A1, 1A3, 2B15, 2B4, 1A4, 2B7, 1A6, 2B10 and 1A9 are present after 6 months of age. There is different in expression of UGT1A1, 1A6 and 2B6 protein but lower mRNA expression for UGT2B4, 1A9 was seen. Hepatic glucuronidation activity in 1-2years is low compared to adults for the following drugs e.g buprenorphine, amitriptyline, ibuprofen, estrone, 4-tert-butylphenol. Acyl co-enzymes A, phospholipid content, fatty acid with long chain and membrane factors may be responsible for enzymatic activities differences between paediatric and adult. In elderly, there is reduced glucuronidation of lamotrigine and elimination of oxazepam, retigabine by UGT activity.
The sulfate conjugation of several endogenous and exogenous chemicals by sulfotransferase(SULT) gene family that encodes about 11 major enzymes using 3'-phosphoadenosine-5'-phosphosulfate(PAPS). In peadiatric, there is maturation of sulfate pathway at conception which is the main metabolic route in infant and children for salicylamide and paracetamol. For example in morphine metabolism sulfate conjugation can compensate for the less-matured glucuronidation.
CONJUGATION WITH AMINO ACIDS
Biotransformation of some compounds is dependent on the conjugation of foreign compounds of carboxylic acids with endogenous amino acids. In humans glycine, glutamine and taurine are amino acids that undergoes conjugation frequently. In paediatric , conjugation with glycine increases from conception to children age and is the major pathway for metabolism of salicylates in neonates. Formation of hippuric acid by glycine conjugation of benzoic acid is present but insufficient in preterm babies.
CONJUGATION WITH GLUTATHIONE
Cytosolic glutathione S-transferase(GST) is responsible for conjugation of glutathione. Catalyses of conjugate of different electrophiles with reduced glutathione is the major way by which GSTs metabolize carcinogens , exogenous and endogenous toxins. In paediatric within 12-24months, there is increase in GSTA1 and GSTA2 expression to adult level with average of 3 fold and GSTM expression increased to about 5 fold to adult level at conception. In adult liver there is no GSTP1 but it is present in neonates. GST activity and GSTP1 level in female only showed important increase from less than fifty years to over 70 years.