TRIPASS XR تري باس

 

Rosenberg, L. E. (1980). Genetic Aspects of Aging. State ofthe Art Lectures: Basic Aspects of

Aging. New Orleans: American College ofPhysicians.

Rossman, I. (1979). The anatomy of aging. In Clinical Geriatrics, ed. Rossman, 1., pp. 3-22.

Philadelphia:J. B. Lippincott Co.

Rowe, J. W., Andres, R., Tobin , J. 0., Norris, A. H. & Shock, N. W. (1976). The effect ofage on

creatinine clearance in man: A cross-sectional and longitudinal study. J. Gerontol.. 31,

155-163.

Srnith, M. J. & Hall, M. R. P. (1973). Carbohydrate tolerance in the very aged. Diabetologia, 9,

387-390.

Tomiinson, B. 0 ., Blessed, G. & Roth, M. (1968). Observations on the brains ofnondemented

old people. J. Ne urol. Sci., 7, 331-356.

Tomlinson, B. E. & Irving, D. (1977). The numbers of limb motor neurons in the human

lumbosacral cord throughout Iife. J. Neurol. Sei.. 34,213-219.

Yan, S. H. Y. & Franks, J. J. (1968). Albumin metabolism in elderly men and women. J. lab.

clin. Med.. 72,449-454.

Weksler, M. E., Innes, J. E. & Goldstein , G. (1979). The role ofthe thymus in the senescence of

the immune response. In Aging and Immunity, ed. Singal, S. K., Sinclair, N. R. & Stiller,

C. R., pp. 165-172. New York: Elsevier/North Holland .

DRUG METABOLISM

AT VARIOUS AGESYOUNG

A.RANE

Department o/Clinical Pharmacology at the Karolinska Institute,

Huddinge Hospital,

S-14186 Huddinge,

Sweden

The elimination processes may be envisaged as a defenee meehanism of the body in

the absence of which drug toxieity would ensue. Most drugs are metabolized before

they are exereted. The traditional eoneept about metabolie reaetions is that of a

deaetivation proeess but an inereasing number of drugs are now known to be

metabolized to aetive or even toxie produets (Drayer, 1976).

Knowledge about qualitative and quantitative aspeets of drug metabolie processes

is essential for a rational drug treatment. This is particularly important in the treatment of infants and ehildren sinee physiological factors whieh partly regulate the

drug disposition are subjeet to continuous ehanges during development.

In vitro datain infantsandfoetuses

Drug metabolie processes may be studied in vitro in tissue speeimens but little

quantitative information about the in vivo elimination has emerged from such

studies. Nevertheless, valuable qualitative information about the metabolie reaetions

may be obtained.

For obvious reasons the in vitro metabolism of drugs may be studied only in

exeeptional situations. A few reports have demonstrated the presenee of the

eomponents of the drug oxidizing enzyme system in the human neonatal liver

(Soyka, 1970). Aranda, MaeLeod, Renton & Eade (1974) demonstrated the same

eomponents as weil as the oxidation of aminopyrine and aniline in liver speeimens

obtained from premature and full-term newborn infants at autopsy or surgery. These

da ta demonstrate the in vitrobasis for the disposition ofdrugs in vivo.

Comparatively more information is available about the in vitro metabolism of

drugs in the unborn infant. The human foetus possesses unique biological properties

in that its liver eontains eaeh ofthe eomponents ofthe microsomal electron transport

system, that is the cytochrome P-~50 system (Yaffe, Rane, Sjöqvist, Boreus &

Orrenius, 1970). Several drugs have been shown to be oxidized in the human foetal

liver already during mid-gestation (Rane & Ackermann, 1972; Rane, Sjöqvist &

Orrenius, 1973; Pelkonen & Kärki, 1973; Rollins, von Bahr, Glaumann, Moldeus &

DRUG METABOLlSM IN THE YOUNG 99

Rane, 1979; Yaffe eral., 1970). Recently it was also shown that the human foetalliver

catalyzes the methylation of theophylline to caffeine (Aranda, Louridas, Vitullo,

Thom, Aldridge, Haber, 1979).

Conjugation reactions have also been studied. Attempts to demonstrate glucuronidation of 4-methylumbelliferone (Hirvonen, 1966; Rane, 1973), I-naphthol,

p-nitrophenol (Rane, 1973), paracetamol (Roll ins er al., 1979) and harmol (Steiner,

von Bahr & Rane, 1980, in preparation) were unsuccessful. On the other hand we

recently showed that conjugation of morphine is catalyzed in human foetal liver

(Pacifici , Säwe, Kager & Rane, 1980, in preparation). This seems to be the first drug

which is reported to be conjugated in the human foetus .

The deficient glucuronidation of most drugs is compensated by early development

of sulphate conjugation (Wengle , 1964). This conjugation pathway is operative with

paracetamol (Roll ins eral., 1979) and harmol (Steiner eral., 1980, in preparation) as

substrates. Other drugs are possibly also conjugated to some extent in the human

foetalliver but very little is known about this at present time.

The sulphate conjugation of paracetamol along with the deficient glucuronidation

of this drug in human foetal isolated hepatocytes (Roll ins er al., 1979) is commensurate with fmdings in the newborn infant. Paracetamol is predominantly

excreted as sulphate conjugate in neonates and only to a minor degree as the

glucuronide (Levy, Khanna, Soda, Tsuzuki & Stern, 1975; Miller, Roberts & Fischer,

1976) whereas the proportion between these metabolites is the reverse in adults

(Howie, Adriaenssens & Prescott, 1977). This points out the potential of foetal in

vitro data to predict semi-quantitatively the metabolie pattern at a later stage of

development.

In vivodatain infantsandchildren

Ethical and practical constraints set a limit to the types of pharmacokinetic studies

that can be performed and that give the best information about drug metabolie

capacity in the infant and child. The most commonly measured parameter is the

plasma half-life (TIf,) of the drug. However, the TIf, does not necessarily reflect the

drug metabolizing capacity (see below).

This is preferably estimated by the clearance term (Cl) which is the volume of

blood or plasma that is irreversibly cleared from the drug per unit time. The easiest

way of measuring drug clearance is to repeatedly analyze the plasma (or blood)

concentrations after a single intravenous (i.v.) or oral (0) dose and measure the area

under the plasma concentration versus time curve (AUe). Ifthe dose is administered

orally a correction factor (F) has to be introduced. F denotes the bioavailability, that

is, the fraction of the oral dose (Do) that reaches the systemic circulation and that is

not bound/metabolized in the liver or the gut wall after absorption. Accordingly

D· (1) CILv.= i.v ,

AUCLv.

ci, F.Do (2)

AUCo

Binding and /or metabolism equals 1- Fand is collectively called 'first pass elimination' or 'first pass effect' (E). It follows that

F= I-E (3)

100 A.RANE

A low value of F indicates a high 'first pass elimination' but ma yaiso be due to

incomplete absorption ofthe drug.

The liver is the most important eliminating organ. If the drug is metabolized only

by the liver then the systemic clearance equals the hepatic clearance (CI H). A

physiological approach to the clearance of drugs in the liver was introduced some

years ago (Rowland, Benet & Graham, 1973; Wilkinson & Shand, 1975). It is weil

established that the extraction ratio over the liver, EH, is a function not on ly of the

hepatic drug metabolizing enzyme activity (Cl , =total 'intrinsic' hepatic clearance)

but also ofthe hepatic blood flow (Q) according to the follow ing equations:

CIH= Q . EH (4)

C1H~Q [Q~~li] (5)

From this it is evident that changes in the liver blood flow will influence the EH and

hence the CI Hto different extents when the Cl, is high or low. Similarly, changes in

the hepatic enz yme activity will result in different effects on the CI H depending on the

value ofCl, (Wilkinson & Shand, 1975). A classification ofdrugs, when possible, into

'Iow extraction' drugs and 'high extraction' drugs according to their Cl, values (low or

high , respectively) makes it easier to interpret what the TI/, of a drug that is

eliminated only by hepatic metabolism really reflects.

Due consideration must also be taken to the drug binding to plasma proteins,

formed blood elements etc , since equation (5) may be expressed as

I f

B • CH ]

[ Q+-fBCli

(6)

where fo denotes the unbound fraction and Cl , the intrinsic hepatic clearance of

unbound drug (Wilkinson & Shand, 1975).

Estimates ofthe Cl , from in vitro da ta as Vmax : Km(Gillette, 1971; Rane, Wilkinson

& Shand, 1977) have limited interest in the absence ofhepatic blood flow data at different ages. In vivo methods to mea sure Cl, are therefore preferred. By defmition, the

oral clearance of a drug (Cl o) that is completely absorbed and completely metabolized by the liver is equivalent to the intrinsic hepatic clearance of the drug. Unfortunately, few clinical situations that permit measurement of Cl , of such drugs

seem to appear, The Tv, must therefore be used as an estimate of the hepatic drug

metabolizing activity, when this is appropriate. It must be kept in mind that the TI/,

ofdrugs that are only eliminated in the liver is also related to the Vd, according to

O.693 .Vd

Tv, (7)

CI H

Provided that the Vd is constant the Tv, will reflect the hepatic enzyme activity (for

'low extraction' drugs) the hepatic blood flow (for 'high extraction' drugs) or both (for

drugs with intermediate values ofCl.). Possible differences in Vd must be taken into

consideration when Tv, da ta are compared between infants, ch ildren and adults. It is

reasonable to believe that the Vd ofmany drugs shows age-dependent variation due to

variation in the fluid and tissue compartments during development.

Besides the Tv; the steady-state concentration (Css) reflects the drug metabolizing

·capacity:

F .O

Css= - - - - - (8)

DR UG MET ABOLlSM IN TH E YOUNG 101

r denotes the dosing interval. This equation ma y be expre ssed as

D

Css (9)

fa .Cl ] , r

if substitution for Fand CI H from equation 6 is made. This equation shows that the

Cssis not a funetion ofthe hepatie blood flow.

It is obv ious that the clinieal situation and the eth ieal eonstraints ereate very few

possibilities to do pharmaeokinetie stud ies in ehildren beyond det erminat ions of the

Css and the Tv; These parameters are of value for estimat ion of the drug metabolie

eapaeity onl y inasmueh as the fra ction that is metabolized is known at the partieular

age ofthe infant or ehild.

Clinical data

Onl y few drugs with known 'low to intermediate extraetion' eharaete risties have been

studied in infants and ehildren. Table I gives the T'I, data for some drugs eon sidered

to belong to this group. The data reveal age-dependent differenees in the T'I, for

tolbutamide, amylobarbitone and mepi vaeaine whereas th is is not found for

earbamazepine and phenytoin. For the latter drugs, howe ver, there had been an

intrauterine exposure of the infant beeause of maternal treatment with these antiepileptic drugs. Therefore , the data may not refleet th e situation in dru g-nai ve

newborn infants.

Table 1 Kinetics in children of drugs considered to belong to the low 'to intermediate

extraction' group.

Drug Plasma orserum half-life(h)* Reference

Newborns Infan ts/ Adults

children

Tolbutamide 10-40 4.4-9.0 Nitowsky et al.(1966)

Amylobarbitone 17.4-59.5 11.6-27.2 Krauer et al.(1973)

(39) (16)

Phenytoin 6.6-34.0 14.5 Rane et al. (1974)

Lund et al. (1 974)

Carbamazepine 8.2-28.1 10.3-20.7 16.4-26.6 Rane et al. (1975)

13.7-18.9 Eichelbaum et al.(1975)

Bertilsson et al. (1 980)

Rane et al.(1976)

Mepivacaine 8.7 3.2 Moore et al.(1978)

* Range and/or mean,

Table 2 summarizes pharmaeokinetie literature data in infants and ehildren of

'high extraetion' drugs . One gets th e impression that the differenees in Tv, are

smaller between ehildren and adults than for the previous group ofdrugs . Sinee under

the eonditions delineated above, the hepatie blood flow is of great er importanee for

the Tv, than the hepatie intrinsie clearanee the data suggest, but do not pro ve, that

there is no pronouneed differenee in the hepatie blood flow between these age groups.

Great interindivi dual variation (20-fold) in the pre-dose pla sma eoneentration of

propoxyphene was observed (Wilson, Atwood & Shand, 197 6) in eonsisteney with the

theoretieal predietion s for 'high-extraction' drugs. This variati on was greater than

that in plasma Tv; whieh was onl y five-fold (Table 2). Th e eorrespondi ng variations

in adults were ten -fold and two-fold, respeetively . It was eoncluded tha t th is drug is

subjeet to extensive 'first-pass elimination' in ehildren just as it is in adults. The need

for individua lized dose adjustments eannot be overemphasized for thi s type ofdrugs .

102 A.RANE

Table 2 Kinetics in children ofdrugs considered to belong to the 'high extraction' group,

Drug Plasma or serum half-life (h)* Reference

Newborns Infants / Adults

children

Morphine

Propoxyphen

Nortriptyline

Lignocaine

Etidocaine

Propranolol

2.7 2.1-2.4 0.9-4.3

(2.7)

1.7-7.7 1.9-4.3

(3.4) (2.5)

17 56

3.2 1.8

6.4 2.6

Great variation between patients in

pre-dose plasma concentration during

steady-state (9.57 ng ml")

Dahlström et al. (1980)

Säweet al.(1980)**

Wilson et al. (1976)

Wolen et al. (1971)

Sjöqvist et al. (1972)

Mihaly et al. (1978)

Mihaly et al. (1978)

Tucker & Mather (1978)

Wilson et al.(1976)

• Range and/or mean.

•• Sawe, Dahlström, Paalzow & Rane (1980), in preparation.

Propranolol was also shown to behave as a 'high extraction' drug in children

(Wilson et al., 1976). The pre-dose plasma eoneentrations varied six-seven-fold in

seven ehildren who reeeived the drug six hourly for long periods.

Morphine kineties have only been studied in ehildren after parenteral administration. Available kinetie data have not revealed significant differenees in TI/, between

infants/ehildren and adults (Table 2).

The kineties ofsome other drugs are listed in Table 3. Theophylline, and in partieular, eaffeine has an extremely prolonged TI/, in newborn infants as eompared to

adults. Caffeine is not exereted unehanged in the urine of adult patients (Axelrod &

Reiehenthal, 1952; Cornish & Christman, 1957) and therefore the Tv, largely refleets

the metabolie clearanee. Aldridge, Aranda & Neims (1979) found, however, that the

unehanged drug comprised more than 85% of the urinary exeretion products in the

newborn. The neonate has a limited ability to metabolize caffeine and does not

aehieve the adult urinary metabolite pattern until the age of eight months. The Tv,

therefore refleets the undeveloped metabolism of eaffe ine as weil as the immature

renal exeretory funetions. Caffeine provides a nice example of an age-dependent

metabolism and illustrates the pitfalls in interpreting TI/, data without knowing the

elimination routes.

Table 3 Kinetics of certain other drugs in different age groups.

Drug Plasma or serum half-life (h) Reference

Newborns Infants/ Adults

children

Caffeine

Theophylline

Oxazepam

Paracetamol

- 96

14.4-57 .7

(30.2)

21.9

3.5

1.4-7.9

(3.7)

- 4

3.5-8 .0

(5.8)

6.5

1.9-2.2

Aldridge et al. (1979)

Aranda et al. (1976)

Ellis et al. (1974, 1976)

Tomson et al. (1979)

Levy et al. (1975)

Miller et al. (1976)

Howie et al. (1977)

It has been suggested (Aldridge et al., 1979) that the low eaffeine metabolizing

capacity in newborn infants is due to its preferential metabolism by the form of

cytoehrome P-450 that is indueible by polyeyclic aromatie hydroearbons. This partieular form has extremely low eatalytie aetivity (measured as aryl hydroearbon

hydroxylase) in the human foetalliver (Peikonen, Kaltiala, Larmi & Kärki, 1973) as

eompared to the phenobarbitone inducible form ofeytoehrome P-450.

DRUG METABOLlSM IN THE YOUNG 103

Table 3 also includes some drugs that are metabolized exclusively through conjugation reactions. Oxazepam conjugation is catalyzed in the newborn baby, although at a slower rate than in adults ifthe T'I, data are accepted to reflect the rate of

conjugation.