Physiologic Factors Associated with Alteration in Theophylline Disposition

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Total body clearance, the product of volume of distribution and elimination rate constant, quantifies theophylline removal from the body. While intrapatient variability in clearance is small (223,229), interpatient variability is large and appears to be from differences in the rate of hepatic biotransformation, which changes with age, concurrent illness, smoking, pregnancy, aberrations in diet, and intake of other drugs. The volume of distribution is a somewhat larger fraction of body weight in infancy and varies inversely with body fat. However, the major variable of the two components of clearance is the elimination rate, often expressed as a half-life of elimination. Because of immature hepatic enzymes, metabolic clearance of theophylline is very slow in the neonate, and even more so in the premature, with elimination half-lives averaging greater than 24 hours. Consequently, dosage requirements are markedly reduced in neonates (194,255) and increase during the first year of life (230). Maturation occurs over the course of the first year of life, so that elimination half-lives average the same from age one to nine and then slowly decrease until mean elimination half-lives in adults average twice that seen in children from one to nine years. Girls begin to have decreased weight-adjusted dosage requirements at a somewhat earlier age than males (97); this decrease in clearance appears to be related to sexual maturation that begins earlier in girls (231).

Conflicting reports have been published on the influence of obesity (189,190,232-235), old age (198,236,237), and gender (238-240) on theophylline clearance. Available evidence suggests that there is no clinically important difference in theophylline clearance between males and females of comparable age and/or development (97,238). Free-drug clearance appears to be lower in elderly patients than in younger adults, because of decreased protein binding (198). The decrease in theophylline clearance

Theophylline Dose Serum Level
Figure 2 Distribution of dosage requirements needed to attain serum theophylline concentrations at various ages. Source: From Ref. 224.

associated with hepatic cirrhosis (195,196), acute hepatitis (241), cholestasis (241), cardiac decompensation (242-244), cor pulmonale (245), hypothyroidism (246), and sepsis with multiorgan failure (247) can be large and of major clinical importance.

Clearance is also reduced during febrile illnesses of various etiology (223,248-251). Fever experimentally induced with etiocholanolone has been shown to reduce the clearance of antipyrine, another drug N-demethylatedby cytochrome P450 1A2 (252). Increased theophylline serum concentrations

Patient age

Figure 3 Comparison of mean dosage requirements needed to attain serum theophylline concentrations between 10 and 20 mg/mL (mean 14 mg/mL) in Iowa during the period from 1978 to 1983 and from 1990 to 1995 at two clinics. The shift to lower doses among all groups indicates decreased population clearance of theo-phylline, presumably from some difference in environmental stimulus of theophylline metabolism; the difference in exposure to active and passive cigarette smoke during these two time periods is postulated to be in the cause of this. Source: From Ref. 224.

Patient age

Figure 3 Comparison of mean dosage requirements needed to attain serum theophylline concentrations between 10 and 20 mg/mL (mean 14 mg/mL) in Iowa during the period from 1978 to 1983 and from 1990 to 1995 at two clinics. The shift to lower doses among all groups indicates decreased population clearance of theo-phylline, presumably from some difference in environmental stimulus of theophylline metabolism; the difference in exposure to active and passive cigarette smoke during these two time periods is postulated to be in the cause of this. Source: From Ref. 224.

have also been associated with herpes simplex viral infection (253). While there has been speculation that viral respiratory infections can reduce theophylline elimination in the absence of fever, extensive clinical experience in young children who got multiple viral respiratory infections while on maintenance therapy with theophylline and controlled studies in adults (254) and children with respiratory syncytial virus infection (255) have not supported any clinically important role for viral infections in the absence of sustained high fever, e.g., >102°F for > 24 hours.

In studies of non-asthmatic volunteers, increased clearance rates have been reported for cigarette and marijuana smokers (239,256). Compared with adolescents of similar age, patients with cystic fibrosis have a greater clearance and shorter elimination half-life of theophylline (261). This could be because of some aspect of their diet or delayed maturation compared with age-matched controls rather than inherently faster metabolism. A high protein, low-carbohydrate diet increases the rate of theophylline elimination, whereas a low protein, high-carbohydrate diet decreases theophylline clearance compared with a normal diet (257,258). Ingestion of charcoal-broiled beef also can increase clearance (259). However, the changes in clearance caused by diet are, on average, not large and are unlikely to require changes in dosage requirements except when radical and persistent

Figure 4 Relationship between changes in steady-state concentration and change in dose among 42 patients who had at least two serum concentration measurements at different doses of the same product (from 200 charts reviewed). In 30 of these children, percent change in serum concentration was at least 50% greater than percent change in dose (% change in concentration divided by % change in dose > 1.5). Thus, dose-dependent kinetics of a sufficient magnitude to be of potential clinical importance occurred in at least 15% of 200 children. Source: From Ref. 226.

Figure 4 Relationship between changes in steady-state concentration and change in dose among 42 patients who had at least two serum concentration measurements at different doses of the same product (from 200 charts reviewed). In 30 of these children, percent change in serum concentration was at least 50% greater than percent change in dose (% change in concentration divided by % change in dose > 1.5). Thus, dose-dependent kinetics of a sufficient magnitude to be of potential clinical importance occurred in at least 15% of 200 children. Source: From Ref. 226.

alterations in diet occur (e.g., a heavy meat eater adopting a high-carbohydrate vegetarian diet or a low protein, hypocaloric diet) (260).

Chronic hypoxia in patients with severe COPD requiring supplemental oxygen was associated with a significantly lower theophylline clearance among patients with a PaO2 of less than 45 mmHg while breathing room air for 48 hours (261). However, administration of supplemental oxygen did not result in an increase in theophylline clearance in those patients, suggesting that the decreased clearance is a function of the disease for which the oxygen is being used rather than the oxygen itself.

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Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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