Oshikoya, Kazeem Adeola
(2014)
Using the caffeine breath test to study drug metabolism in protein-energy malnourished children.
PhD thesis, University of Nottingham.
Abstract
Malnutrition is a global health problem that affects infants and young children. It is frequently associated with infections and commonly affects children in developing countries. Malnutrition is the cellular imbalance between the supply of energy from macronutrients and micronutrients and the demand of the body for them in order to achieve normal growth, maintenance, and specific functions. Underweight (mild to moderate) and marasmus, marasmic-kwashiorkor, and kwashiorkor (severe) are the spectrum of malnutrition.
Various pathophysiological changes, including fatty changes, abnormal rough endoplasmic reticula and mitochondria, decreased peroxisomes, and decreased quantity and quality of metabolising enzymes, are associated with malnutrition which may significantly influence hepatic drug metabolism. However, the effect of different categories of malnutrition on drug metabolism has not been extensively investigated. This research, therefore, aimed to determine the effect of malnutrition on drug metabolism. The specific objectives are (i) to perform a systematic review of the studies of drug pharmacokinetics in malnourished children, and (ii) to use the caffeine breath test to determine the effects of different types of malnutrition on the metabolising activity of hepatic CYP1A2 enzymes.
The systematic review involved literature searches in the MEDLINE and EMBASE databases covering publications between January 1960 and December 2009. Articles describing drug pharmacodynamics and pharmacokinetic parameters in the four categories of malnutrition, limited to children from 0 to 17 years, were sought using both databases and by reference tracking. Altogether, 42 publications evaluated the disposition of 34 drugs in malnourished children. The drug absorption rate (Ka) was reported for eight drugs, of which gentamicin, metronidazole, phenytoin, chloramphenicol, paracetamol, and sulphamethoxazole showed no difference in the values of Ka for malnourished children and the control groups. The AUC of seven drugs did not differ for malnourished children when compared to their control groups but significantly decreased for carbamazepine (p < 0.05) and chloroquine (p < 0.001). By contrast, there was a statistically significant increase in the AUC of six drugs: metronidazole (p < 0.05), caffeine (p < 0.05), paracetamol (p < 0.05), phenobarbitone (p < 0.05), sulphadiazine (p < 0.01), and sulphamethoxazole (p < 0.001). The plasma protein binding of 19 drugs was evaluated in seven in vitro and two in vivo studies. There was a statistically significant decrease in the protein binding of 17 drugs in kwashiorkor when compared to healthy adults (p-values ranged from <0.0005 to <0.05). Nineteen studies evaluated the effects of malnutrition on the volume of distribution (VD) for 14 drugs. For most drugs, malnutrition had no statistically significant effect on VD. However, four drugs: gentamicin, quinine, streptomycin, and theophylline demonstrated contrasting results. The effect of malnutrition on the total clearance (CL) and elimination half-life (t½) of nine drugs that are primarily metabolised in the liver was evaluated in 15 studies. There was a statistically significant decrease in the CL of six drugs: acetanilide (p < 0.025), antipyrine (p < 0.05, p < 0.0025, p < 0.05), caffeine (p < 0.01), sulphamethoxazole, isoniazid (p < 0.01), and metronidazole (p < 0.01). There was a corresponding statistically significant increase in their plasma half-lives. For six drugs that are primarily eliminated by the kidneys, malnutrition has a varying effect on their total CLs. The total CL was significantly increased for penicillin in children with marasmus (p < 0.001), marasmic-kwashiorkor (p < 0.01), and kwashiorkor (p < 0.01), as well as increased for streptomycin in children with kwashiorkor (p < 0.01). By contrast, the total CL was significantly decreased for penicillin in underweight children (p < 0.01). It was also significantly decreased for cefoxitin in children with kwashiorkor (p < 0.025). The significantly decreased total CL of most of the drugs primarily metabolised by the liver may reflect decreased activity of the intrinsic hepatic metabolising enzymes. This would suggest a need to reduce drug dosage in malnourished children. More studies are therefore required to assess the activities of the hepatic metabolising enzymes in malnourished children.
Following the systematic review, the caffeine breath test (CBT) identified as a non-invasive approach to study the effects of the four categories of malnutrition on caffeine metabolism. Caffeine is a 1, 3, 7 trimethylxanthine compound that is metabolised in the liver by 1-N, 2-N and 7-N demethylation, and C-8 hydroxylation to 1, 3, 7 trimethyluric acid. CYP1A2 is responsible for the 3-N demethylation of caffeine. The CBT involves oral administration of a non-radioactive stable isotope of caffeine (13C on the 3-methyl group). The caffeine undergoes 3-N demethylation in the liver which is a CYP1A2 dependent reaction. After N-demethylation, the 13C methyl group enters the carbon pool as it is converted to formaldehyde, formate and bicarbonate. The bicarbonate is exhaled as carbon-dioxide. The exhaled labelled 13CO2 is known to correlate with CY1A2 activity.
Fifteen children each who were underweight or experiencing marasmus, marasmic-kwashiorkor or kwashiorkor were recruited from Lagos and Kano States in Nigeria. They were studied before and after nutritional rehabilitation. After ingesting labelled caffeine (3mg/kg) at 0900 hours, breath samples were collected in duplicate at -20, -10, -1 minute and every 15 minutes over 2 hours. The cumulative mean percent 13C-caffeine dose exhaled as 13CO2 was measured over 2 hours. Student’s t-test was used to compare the results for each category of malnutrition, before and after nutritional rehabilitation, at 5% level of significance. The mean cumulative percent 13C-caffeine dose recovered (CPDR) in underweight children was 7.56 ± 4.01% and 7.95 ± 3.68% before and after nutritional rehabilitation, respectively, and there was no significant difference in the mean values (p = 0.603). The CPDR significantly increased after nutritional rehabilitation in children with marasmus (from 6.80 ± 3.00% to 7.67 ± 2.81%, p < 0.001), marasmic-kwashiorkor (from 6.61 ± 2.26% to 7.56 ± 2.46%, p < 0.041), and kwashiorkor (from 6.29 ± 1.06% to 7.20 ± 1.80%, p =0.002). It is concluded that the present study may not have been adequately powered to detect a statistically significant difference in the results for underweight children. Such a difference would have been the basis for validating the results in a larger population of underweight children. However, doses of drugs that are metabolised by CYP1A2 enzyme may require modification in severely malnourished children.
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