Drug metabolism and ageing.

Important changes in drug metabolism occur with ageing. Age-associated reductions in function of some but not all cytochrome P450 enzymes (CYPs) have been described. Induction and inhibition of CYPs needs to be revisited in light of recent advances. The function and pharmacology of transporters have not yet been examined for an age-related effect. Finally, the concept of frailty is being underpinned by studies documenting a decline in drug metabolism and changes in disposition in frail older people compared with either healthy elderly or the young.

Clinical pharmacology of old age syndromes.

Several syndromes occur in old age. They are often associated with increased mortality and in all there is a paucity of basic and clinical research. The recent developments in the clinical pharmacology of three common syndromes of old age (delirium, urinary incontinence, and falls) are discussed along with directions for future research.

Acute confusion secondary to pneumocephalus in an elderly patient.

PRESENTATION: an 83-year-old man was admitted to hospital with acute confusion 3 days after a direct flight from Australia. OUTCOME: computed tomography (CT) brain scan and magnetic resonance imaging head scan revealed the cause to be pneumocephalus, apparently the result of barotrauma caused by Valsalva manoeuvres when he attempted to unblock his nose during the flight. After 5 days of nursing in the vertical position the patient's Abbreviated Mental Score returned to normal. A CT brain scan 6 weeks later showed complete resolution of the pneumocephalus.

Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A.

BACKGROUND: Cytochrome P4503A (CYP3A) activity exhibits considerable interindividual variability, and an in vivo probe to measure such differences would serve several purposes. The erythromycin breath test (ERBT) is an established approach that has proven useful in this regard, but it has several limitations. More recently, the hydroxylation of midazolam has been suggested as an alternative in vivo probe approach, because it is possible to estimate CYP3A activity in the intestinal epithelium as well as in the liver. The purpose of this study was to investigate the relationship, if any, between the ERBT and midazolam's CYP3A-mediated metabolism. METHODS: Twenty healthy, medication-free young (24 to 46 years) European Americans (10 women) each received on separate days, in random order, either 3 microCi [14C-N-methyl]-erythromycin intravenously, 1 mg midazolam intravenously, or 2 mg midazolam orally. An ERBT value was determined 60 minutes after administration, and clearances were estimated after midazolam administration. In addition, an endogenous 0- to 4-hour urinary 6beta-hydroxycortisol/cortisol ratio was measured. RESULTS: All three measured drug trait values varied approximately threefold to fivefold, whereas the endogenous phenotype measure exhibited far greater variability (>100-fold). No statistically significant (P < .05) correlations existed between any of the trait values, including the ERBT value, obtained after intravenous administration of the radiolabeled probe and the systemic clearance of midazolam, expressed in terms of either total or unbound drug, or on an absolute or a body weight-corrected basis (r = 0.03 to r = 0.24; P = .08 to P = .90). Substratification according to sex generally did not improve such relationships. CONCLUSION: Although both erythromycin N-demethylation and the metabolism of midazolam by hydroxylation are mediated by CYP3A, the phenotypic trait measures associated with these two in vivo probe drugs do not provide the same information about the catalytic activity of the enzyme. An indirect measure such as the ERBT may reflect CYP3A activity and be useful for some purposes, but the estimation of the oral and intravenous clearance of midazolam has additional advantages, and they may be more applicable and have broader usefulness as quantitative estimates of CYP3A activity.

'Not for resuscitation': guidelines for decision making and documentation.

In 1991, the government's Chief Medical Officer made it clear that the responsibility for resuscitation policy lay with consultants, and that they should ensure this policy was understood by all staff caring for a patient, in particular junior medical staff. Since then, many hospitals and trusts have provided members of the multidisciplinary team with guidance on how to ensure that adequate and satisfactory communication is in place to record a patient's resuscitation status. However, as is common in the NHS, poor documentation is still evident. Guy's & St Thomas' Hospital Trust has been using a document since April 1998 which is clearly written, user friendly and does not contain ambiguous statements. With ongoing audit of this policy document we hope to reduce the incidence of inappropriate resuscitation attempts which are costly, both emotionally and financially, for all concerned.

Use of COOP charts in the day hospital.

The day hospital is an essential component of health service provision for the elderly. Demonstrating out-come improvement has not been uniformly successful. COOP charts have been validated in general practice as a tool to demonstrate improvement in functional activity. Therefore the aim of this study was to examine the usefulness of the COOP system in measuring change to a rehabilitation program in an elderly care day hospital. Thirty elderly patients (F/M: 24/6 with age range 75-91 years) attending the day hospital for rehabilitation for musculoskeletal (25) or neurological (5) problems were asked to complete COOP charts during the first or second attendance and after treatment had been completed. A fall in COOP score indicates improvement. The total COOP score improved from 27.9+/-4.3 to 22.5+/-4.0 (C.I.=3.8-6.9; t value=7.2; P<0.0001). Significant improvement was documented in 7 out of 9 individual areas of function/aspects of daily living. The results show that COOP charts, which are easy to administer, may be useful in monitoring change in elderly patients attending day hospital for rehabilitation.

Clinical pharmacokinetic considerations in the elderly. An update.

There are a number of areas in which advances have been made over the last few years in the area of pharmacokinetics in the elderly. There is increasing understanding of the diversity of cytochrome P450s (CYP) and the variability of the age-related decline in CYP activity. This has helped to explain some of the interindividual variability in drug metabolism with age. The importance of ethnic differences has emerged, but specific work is needed in this area in the elderly. Differences in the handling of chiral compounds has been reported but as yet no clinically important findings that may lead to a change in clinical practice have emerged. The emerging importance of extrahepatic drug metabolism, especially in the intestine, has added a new complexity to our understanding of pharmacokinetics. The issue of frailty is also discussed in this article. Whether it will be of value at the bedside has yet to emerge. Nonetheless, as a concept, recent data has supported its potential use to define those more at risk of clinically meaningful pharmacokinetic alterations. Other advances have included the appreciation that selectivity in induction and inhibition in the elderly are due to the existence of multiple CYP forms. Similarly, the role of these various enzymes in disease is also improving our clinical understanding, as exemplified in Parkinson's disease.

Differences in clearance and sensitivity to Triazolam in American blacks as compared with whites

BACKGROUND: Inter-ethnic differences exist in both pharmocodynamics and pharmocokinetics. CYP3A is the most abundant cytochrome P450 enzyme in human liver and is responsible for the metabolism of a large number of drugs and xenobiotics. AIM OF STUDY: The purpose of the present study was to determine whether there are differences in the metabolism and drug responsiveness to triazolam, a substrate of CYP3A, in American blacks and whites. METHODS: Eight American blacks and eight age - and body weight- matched whites receved orally a triazolam 0.375 mg tablet in a double-blind placebo-controlled randomized study. Plasma concentrations and effects of triazolam were measured at multiple time points over 24 hours. The pharmacodynamics of triazolam were examined by measurement of postural sway, digital symbol substitution testing (DSST), and a visual analog scale (VAS) of drowiness. Sensitivity, or the drug effect at a given concentration, was determined. RESULTS: Following oral administration of triazolam, the AUC was significantly lower in blacks (625 +- 160 ng/ml/min) (P<0.05). The systemic clearance of triazolam was three and a half fold higher in blacks (6.6 +- 2.0 vs 1.8 +- 0.2 ml/min/kg in whites, P<0.05) resulting in a shorter elimination t 1/2 (98 +- 24 vs 199 +- 29 min, P<0.05). Triazolam significantly increased postural sway and drowsiness and impaired DSST in both groups. However, there was no significant differences between the two groups in drug effects such that a similar effect of triazolam was observed in blacks with lower plasma concentration. When compared to whites, the sensitivity to triazolam was significantly higher in blacks (P<0.05). CONCLUSIONS: This study demonstrates increased clearance and increased sensitivity to triazlam in American blacks. These findings may have major therapeutic implications in a racially diverse population. (AU)

Decreased intestinal CYP3A in celiac disease: reversal after successful gluten-free diet: a potential source of interindividual variability in first-pass drug metabolism.

BACKGROUND: Cytochrome P450 (CYP) 3A is constitutively expressed in human intestinal villi and may account for significant "first-pass" prehepatic metabolism of a number of drugs in the intestine. Celiac disease results in small intestinal atrophy. We hypothesized that this would result in a loss of CYP3A. METHODS: Formalin-fixed jejunal biopsy specimens taken from nine patients with celiac disease at variable times before and after treatment with a gluten-free diet were immunoperoxidase stained after incubation with anti-CYP3A4 rabbit antisera (1:2000 dilution). The amount of immunoreactive CYP3A was determined by two observers who were blinded to the treatment states of the patients. Staining intensity was graded on a numerical scale from 1 to 4+ on the basis of intensity of staining in individual enterocytes, as well as the total number of enterocytes stained. RESULTS: Slides of biopsy specimens from all nine untreated patients with celiac disease were graded 1. Treatment with a gluten-free diet was associated with a significant increase in CYP3A immunoreactive protein in small bowel biopsy specimens (p < 0.05, Wilcoxon signed-rank test). CONCLUSIONS: We conclude that patients with celiac disease have low intestinal CYP3A immunoreactivity and that treatment with a gluten-free diet is associated with an increase in intestinal CYP3A immunoreactive protein. Our findings suggest that intestinal disease and variability in intestinal CYP3A activity might be an unexamined variable that may contribute to interindividual variability in drug disposition.

Comparison of the dapsone recovery ratio and the erythromycin breath test as in vivo probes of CYP3A activity in patients with rheumatoid arthritis receiving cyclosporine.

INTRODUCTION: Cytochrome P4503A (CYP3A) is primarily responsible for the metabolism of cyclosporine and that of many other drugs. Several substrates of CYP3A have been investigated for use as pharmacologic probes to predict the CYP3A-metabolizing capacity of an individual and, therefore, the disposition of other CYP3A substrate drugs. One such measure of CYP3A activity is the 14C erythromycin breath test, which has been applied to the prediction of cyclosporine disposition. However, the test has practical limitations. Because of this, the 0- to 8-hour urinary dapsone recovery ratio has been studied as an alternative and more practical probe of CYP3A activity. METHODS: The dapsone recovery ratio and the 14C erythromycin breath test were correlated with cyclosporine concentrations in 16 patients with rheumatoid arthritis to determine the usefulness of the dapsone recovery ratio as an alternative to the 14C erythromycin breath test. The erythromycin breath test showed a fourfold variation between subjects and correlated weakly with trough cyclosporine concentrations (r = -0.50, p < 0.05), whereas the dapsone recovery ratio varied only approximately twofold between subjects and did not correlate with trough cyclosporine concentrations (r = 0.02, p = 0.94). The correlation between the dapsone recovery ratio and the erythromycin breath test (r = 0.22, p = 0.41) was not significant. CONCLUSIONS: These data suggest that results obtained with one probe in vivo may not apply to another CYP3A substrate. The poor quantitative relationship between cyclosporine concentrations and the erythromycin breath test limits its usefulness in the prediction of an individual's cyclosporine dose requirement.

Triazolam pharmacokinetics and pharmacodynamics in Caucasians and Southern Asians: ethnicity and CYP3A activity.

A threefold higher area under the plasma drug concentration-time curve (AUC) of nifedipine, a substrate of cytochrome P4503A (CYP3A), has been shown in Southern Asians when compared with Caucasians. To determine if these differences are specific to nifedipine or apply to other substrates of CYP3A, we examined the pharmacokinetics and pharmacodynamics of 0.375 mg triazolam, another substrate of CYP3A, in eight healthy Caucasians and eight healthy Southern Asians in a double-blind placebo-controlled study. When compared with Caucasians, Southern Asians achieved higher maximum plasma concentration (Cmax) (8.0 +/- 2.6 vs 4.8 +/- 1.9 ng ml-1; the 95% confidence interval (CI) of the mean difference was 0.76 to 5.7; P < 0.01) and had a shorter time to reach maximal concentration (tmax) (45 min (range 30-75) vs 90 min (range 60-145); the 95% CI of the mean difference was -69 to -20; P < 0.002). Triazolam AUC, clearance and partial metabolic clearance did not differ significantly between Southern Asians and Caucasians. Significant differences were found in postural sway after triazolam when compared with placebo in both Caucasians (double stance: eyes open (DSEO): 172.9 +/- 82.9 vs 1138.9 +/- 1182.4; the 95% CI of the mean difference was -1897.2 to -34.4; P < 0.04; and Southern Asians (DSEO: 216.2 +/- 80.9 vs 1086.0 +/- 827.1; the 95% CI of the mean difference was -1564.2 to -175.6; P = 0.02; double stance: eyes closed (DSEC): 207.5 +/- 89.8 vs 1156.9 +/- 932.1; the 95% CI of the mean difference was -1718.5 to -178.5; P = 0.02; with no significant difference between the two ethnic groups. These results suggest that the large inter-ethnic difference in nifedipine clearance are not generalizable to all CYP3A4 substrates.

Hawksley random zero sphygmomanometer versus the standard sphygmomanometer: an investigation of mechanisms.

There has been recent controversy over the accuracy of the Hawksley random zero sphygmomanometer (RZS). In most instances, there has been a bias towards lower recordings with the RZS. In an attempt to identify the mechanism, we designed a study to test the hypothesis that biased error is due to: (1) the magnitude of the random zero; and (2) the magnitude of the pressure being recorded. A RZS (60 mm Hg zero UK version) was connected via a Y-tube to a standard mercury sphygmomanometer (SMS). The circumference of the cam responsible for the variable reservoir size in the RZS was marked into quarters. Within each 10 mm Hg band from 300 to 60 mm Hg, 12 paired readings were taken randomly: three within each of the four quarters of the cam circumference. The mean SMS value was 148.8 vs. 148.2 mm Hg for the RZS. Although of minimal biological significance this difference was highly significant (t = 6.2; p < 0.0001). Our findings fail to confirm the difference between RZS and SMS previously reported and we did not find any evidence of a relation in the difference between SMS and RZS and either the random zero value or the height of the blood pressure. Our findings suggest that if the RZS does under record BP versus the SMS it may relate to a patient-machine interaction not detectable in our system.

Metabolism of cytochrome P4503A substrates in vivo administered by the same route: lack of correlation between alfentanil clearance and erythromycin breath test.

Because there is considerable interindividual variation in both microsomal CYP3A4 activity and CYP3A4 substrate disposition, an established probe of in vivo CYP3A4 activity would represent an important advance in clinical practice. In a previous study, no correlation was found between the 14C-erythromycin breath test and urinary dapsone recovery ratio. However these drugs were administered by different routes, with the orally administered dapsone being exposed to presystemic metabolism by the gut and renal metabolism before the measurement of the urinary ratio. To overcome the variable of route of administration, the aim of this study was to determine whether the elimination of two intravenously administered CYP3A4 substrates (alfentanil and erythromycin) correlate. We compared the metabolism of alfentanil to its CYP3A4-dependent metabolite, noralfentanil, with the erythromycin breath test in 14 young healthy white men. No significant correlation was found between alfentanil metabolism and the erythromycin breath test: alfentanil clearance versus erythromycin breath test, r = 0.45, p = 0.1; partial metabolic clearance to noralfentanil versus erythromycin breath test, r = 0.35, p = 0.23. Because these two CYP3A4 substrates were administered by the same (intravenous) route, we conclude that differences in the route of administration do not explain the lack of correlation between the erythromycin breath test and other probes of CYP3A4 metabolism.

Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men.

In vitro studies with human liver microsomes have shown that erythromycin N-demethylation, dapsone N-hydroxylation, and the 6 beta-hydroxylation of cortisol are all primarily mediated by P4503A4. Trait measurements to assess the in vivo level of activity of these separate oxidations have also been developed previously. This study investigated the relationships among the three phenotypic trait measurements in 30 young healthy white men. The frequency distributions of the trait values were all unimodal, with a twofold range for the erythromycin breath test and the urinary dapsone recovery ratio; the urinary 6 beta-hydroxycortisol/cortisol ratio was more variable, with a 17-fold range of values. No statistically significant correlations were observed among any of the trait measurements (dapsone recovery ratio versus erythromycin breath test: r = -0.07, p = 0.7; urinary 6 beta-hydroxycortisol/cortisol ratio versus erythromycin breath test: r = -0.12, p = 0.6; urinary 6 beta-hydroxycortisol/cortisol ratio versus dapsone recovery ratio: r = 0.13, p = 0.5. This lack of any relationship was unexpected and the reason(s) is unknown; however, it is possible that factors such as route of administration and extrahepatic metabolism in the intestinal epithelium and kidney are involved. Further studies are required to identify and validate the use of an appropriate in vivo probe of P4503A4 in humans.

Computerised psychomotor performance testing: a comparative study of the single dose pharmacodynamics of minaprine and amitriptyline in young and elderly subjects.

The psychomotor and cardiovascular effects of minaprine 100 mg, a novel antidepressant, were compared with amitriptyline 25 mg, as a positive control, and placebo in a single dose randomised double-blind crossover trial using an automated psychomotor test battery (APT), postural sway (PS), blood pressure (BP) and pulse in nine young and nine elderly healthy subjects. Analysis of variance, taking into account baseline values, showed that continuous attention test (CAT), critical flicker fusion threshold (CFFT), decision making test (DMT) and paired word association (PWA) were significantly impaired with amitriptyline compared with minaprine and placebo. Minaprine did not differ from placebo. Amitriptyline significantly lowered supine systolic blood pressure (BP) and all treatments produced significant decreases in heart rate in young and elderly. No age effect on psychomotor performance was seen. Minaprine compared favourably with amitriptyline using the APT with the doses used. The APT is useful in the evaluation of new drugs on psychomotor performance.

Newer agents for the treatment of malignant hypercalcemia.

The treatment of malignant hypercalcemia has involved fluids, diuretics, and specific calcium-lowering therapy with mithramycin and calcitonin. However, newer agents have recently been approved for the treatment of hypercalcemia due to malignancy. This review will discuss three such agents, gallium, etidronate, and pamidronate. This review will concentrate on the clinical pharmacologic characteristics and the clinical trials of these newer agents. Their use in the clinical practice will be suggested based on review of the published literature.

Metabolic changes during serial squash matches in older men.

We have previously reported dramatic changes in heart rate and blood biochemistry in older men during and shortly after competitive squash. In this study we sought to determine whether these changes are attenuated or exaggerated during tournament matches played in rapid succession. Ten veteran (greater than 45 yrs) players were studied during three competitive matches played over a 36-hr period. Squash was associated with significant changes in heart rate and circulating concentrations of catecholamines, lactate, free fatty acids, and potassium. These changes were of equal magnitude and in some cases tended to be exaggerated during the second and third matches. These data confirm the acute changes in cardiac function and metabolism that occur during competitive squash and suggest that these responses are not down-regulated but may in fact be accentuated during sequential tournament matches.