114 R.E. YESTAL

Table 3 Effect of age and smoking on the pharmacokinetics of propranolol (from data of

Vestal et al., 1979).

Apparent

Ageand Number Volume of Systemic Intrinsic liverblood

smoking 0/ TV2 distribution clearance clearance jlow

group subjects (h) (litre kg") (mI kg:' min:') (ml kg"!min') (mI kg:! minr')

Younger(Age21-37)

Nonsmokers 6 4.5±0.36 3.82±0.339 1O.6± 1.31 24.4± 4.20 19.1± 1.82

Smokers 7 3.6±0.39 4A3±0.552 14.9± 14.7 65.5± 1O.05d 20.0±2.11

Total 13 4.0±0.29 4.18±0.341 12.9± 1.14 46.5± 8.10 19.6± 1.36

Older(Age 46-73)

Nonsmokers 6 5.6±0.64 4.24±OA74 9.0±0.91 26.8± 5.59 14.7± 1.68

Smokers 8 4.7±0.53 4.22±0.453 1O.4±O.72b 35.3± 3.61' 15.4± 1.40

Total 14 5.1±OAla 4.23±0.315 9.8±0.58c 31.6± 3.23 15.1± 1.04c

Data shown are mean ± s.e. mean.

a Significantly different from younger group (P < 0.05).

b Significantly different from younger smokers (P < 0.005). cSignificantly different from younger group (P < 0.025).

d Significantly different from younger nonsmokers(P < 0.005).

e Significantly different from younger smokers (P < 0.025).

More direct support for this explanation is provided by the recent report of

Schneck, Luderer, Pritchard, Vary, Dewitt, Bew & Hayes (1980) who examined the

influence of dose on the intrinsic clearance of propranolol in four healthy elderly

(mean age 71 years) and six healthy young subjects (mean age 27 years) using single

20-, 40-, and 160 mg doses. All subjects were nonsmokers. Mean intrinsic clearance

(litres h-1

) was lower in the elderly group when compared to the younger population

at all doses (244 ± 58 vs. 515 ± 142 at 20 mg; 323 ± 116 vs. 459 ± 146 at 40 mg; and

178 ± 54 vs. 232 ± 57 at 160 mg). In the elderl y group there were no significant

difTerences in the intrinsic clearance among doses. In contrast, in the young group

intrinsic clearance decreased significantly with increasing dose. Thus, an efTect of age

on intrinsic clearance was demonstrated at the lowest dose (20 mg), while at the

highest dose (160 mg) there was no significant difTerence between the two age groups.

These data are certainly compatible with the conclusion that in nonsmokers the

efTect ofage on the hepatic metabolism ofpropranolol is a dose-related phenomenon.

Data analysis

A caution in regard to data analysis is warranted. If the age distribution of subjects

conforms best to abimodal distribution, that is, the subjects are mainly either young

or old with few or no middle-aged individuals, the application of linear regression

analysis and the use of correlation coefficients to describe the data is questionable.

This kind of analysis requires a bivariate normal distribution of the dependent and

independent variable (Snedecor & Cochran, 1967). If this condition is not satisfied,

other statistical methods such as group comparisons should be applied to the data. If

data from the middle-aged group are not available, it should not be assumed that they

must necessarily be intermediate between the young and the old. They might weIl be

similar to either the young or the old group. Also, it should be emphasized that the

mere fact of a significant correlation does not necessarily imply a cause and efTect

relationship. It does suggest that there is an association between the variables which

might be tested in a prospective manner. As noted above, it is possible that agerelated variables , rather than age perse, may account for an apparent efTect ofage .

DRUG MET ABOLlSM STUDIES IN THE ELDERLY

Conclusions

115

Available studies on drug disposition in the elderly indicate that age difTerences can

be demonstrated for some drugs. Whether these difTerences can be attributed to the

ageing phenomenon or whether they result from selective mortality is uncertain and

could only be determined with certainty by careful longitudinal studies. DifTerences

in the criteria for subject selection, drug dose and route of administration may

explain the conflicting results ofstudies which aim to examine the efTectof age on the

metabolism of the same drug. These considerations also apply to studies of drug

response wh ich are further complicated by the need to control for age difTerences in

drug disposition.

Acknowledgements

The author gratefully acknowledges support from the Medical Research Service of

the Veterans Administration and wishes to thank Ms . Mary Bettinger for her able

secretarial assistance.

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