Acute renal failure and glomerulopathy caused by nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs are now one of the most common causes of acute renal failure (ARF). To define more clearly the magnitude of the problem, we reviewed all cases of ARF in the Reno (Nev) area from 1972 through 1986. Twenty-seven cases of ARF and seven cases of glomerulopathy were identified, primarily during the last 5 years of the study period. Twenty-three of the cases of ARF and six of the cases of glomerulopathy cleared an average of 23 and 118 days, respectively, after treatment with the nonsteroidal anti-inflammatory drug was stopped. Two cases of ARF persisted, and two patients died. Proteinuria, hematuria, and casts were prominent in both ARF and glomerulopathy but were more pronounced in the glomerulopathies. The treatment of choice is to stop the use of the nonsteroidal anti-inflammatory drug. The role of steroids has not been evaluated.

Acetylator phenotype and genotype in patients infected with HIV: discordance between methods for phenotype determination and genotype.

The acetylator phenotype and genotype of AIDS patients, with and without an acute illness, was compared with that of healthy control subjects (30 per group). Two probe drugs, caffeine and dapsone, were used to determine the phenotype in the acutely ill cohort. Polymerase chain reaction amplification and restriction fragment length polymorphism analysis served to distinguish between the 26 known NAT2 alleles and the 21 most common NAT1 alleles. The distribution (%) of slow:rapid acetylator phenotype seen among acutely ill AIDS patients differed with the probe substrate used: 70:30 with caffeine versus 53:47 with dapsone. Phenotype assignment differed considerably between the two methods and there were numerous discrepancies between phenotype and genotype. The NAT2 genotype distribution was 45:55 slow:rapid. Control subjects, phenotyped only with caffeine, were 67:33 slow:rapid versus 60:40 genotypically. Stable AIDS patients, phenotyped only with dapsone, were 55:45 slow:rapid versus 46:54 genotypically. Following resolution of their acute infections, 12 of the acutely ill subjects were rephenotyped with dapsone. Phenotype assignment remained unchanged in all cases. The distribution of NAT1 alleles was similar in all three groups. It is evident from the amount of discordance between caffeine phenotype and dapsone phenotype or genotype that caution should be exercised in the use of caffeine as a probe for NAT2 in acutely ill patients. It is also clear that meaningful study of the acetylation polymorphism requires both phenotypic and genotypic data.

N-acetylation among HIV-positive patients and patients with AIDS: when is fast, fast and slow, slow?

BACKGROUND: The discrepancy between genotype and expressed phenotype of the polymorphic N-acetyltransferase (NAT2) has been suggested by separate genotypic and phenotypic studies in populations with human immunodeficiency virus (HIV). Only one study has examined both genotype and phenotype in the same population, and no discrepancies were observed. METHODS: In a cross-sectional study, 105 HIV-positive patients and patients with acquired immunodeficiency syndrome (AIDS) were phenotyped for NAT2 activity with use of caffeine as an in vivo probe; 50 of these patients were also genotyped by restriction mapping and allele-specific amplification. In a longitudinal study, 23 patients were phenotyped at least twice during the 2-year study. RESULTS: The distribution of the NAT2 phenotype among the 105 patients was unimodal and skewed toward slow acetylators as opposed to the bimodal distribution observed in healthy white populations. The genotype distribution was 26:24 slow:fast. There were 18 discrepancies between genotype and phenotype: 12 slow acetylators with fast genotypes and six fast acetylators with slow genotypes. No drug-related effects on NAT2 activity were apparent, but the role of disease progression was evident. Among the slow acetylators whose genotype was fast, the incidence of AIDS was higher (six of 12) than that among the fast acetylators whose genotype was fast (two of 14). Among patients phenotyped more than once (mean time between samples, 10.4 months) changes in phenotype from fast to slow were associated with progression of HIV infection. CONCLUSIONS: Disease progression in HIV infection and AIDS may alter expression of the NAT2 gene. The genotype and the phenotype are not interchangeable measurements. In the HIV population, to know the genotype is useful only if the phenotype is also known and vice versa.

Kinetics, distribution, and biotransformation of the chemical HI-6 in the rat, dog, and rhesus monkey.

Disposition of the bis-pyridinium mono-oxime, HI-6, following intramuscular injection in rats (200 mg/kg bw), beagle dogs (10 and 50 mg/kg bw), and rhesus monkeys (50 mg/kg bw) revealed that the oxime was absorbed rapidly and completely from the site of injection, was distributed rapidly in the tissues, and that tissue concentrations decreased below the limits of detection by 4 h after treatment. No overt signs of toxicity were observed in any species at the concentrations given. Tissue analysis for HI-6 and degradation products was conducted by extraction followed by ion-pair, reverse phase, HPLC chromatography. The estimated plasma half-life values were 20, 40-55, and 25-30 min for rats, dogs, and monkeys, respectively. HI-6 and the degradation products were excreted via the urine. A marked species difference in disposition was observed in that HI-6 selectively accumulated in the diaphragmatic muscle of the rat to a level 10- to 20-fold higher than the level in blood plasma, whereas in the dog and monkey, diaphragmatic concentrations were comparable with those in the plasma. Three degradation products of HI-6 were detected in the plasma of the three species. One excreted product formed spontaneously since it was also detected in buffered solutions used for abiotic stability studies. The second product, the picolinic acid analog of HI-6, appeared to be metabolically formed in vivo. A third product remains unidentified.

Determination of p-aminosalicylic acid and its N-acetylated metabolite in human urine by capillary zone electrophoresis as a measure of in vivo N-acetyltransferase 1 activity.

A capillary zone electrophoresis method has been developed for the determination of p-aminosalicylic acid (PAS) and its metabolite, N-acetyl-p-aminosalicylic acid (N-acetyl-PAS), in urine. A linear relationship was observed between time-normalized peak area and the concentration of the parent and metabolite with correlation coefficients greater than 0.9990. The method could be applied to the determination of PAS and N-acetyl-PAS in human urine without any sample pretreatment. A good separation of the analytes is achieved in a run time of 12 min (15 min total, including capillary wash). Using PAS as a probe for N-acetyltransferase 1 activity, 20 healthy volunteers were phenotyped after oral administration of a 1 g dose. The preliminary results seem to indicate a bimodal distribution of N-acetyl-PAS/PAS molar ratios.

Genotype and phenotype of cytochrome P450 2D6 in human immunodeficiency virus-positive patients and patients with acquired immunodeficiency syndrome.

OBJECTIVE: To examine the distribution of the cytochrome P450 (CYP) CYP2D6 phenotype and its relation to genotype, concomitant medication, and disease state in human immunodeficiency virus (HIV)-positive patients. DESIGN: A cross sectional study with a longitudinal component compared individual genotypes for CYP2D6 to the CYP2D6 phenotype. METHODS: Sixty-one predominately male Caucasian, HIV-positive patients were recruited and CYP2D6 genotypes [extensive metabolizer (EM) or poor metabolizer (PM)] determined by polymerase chain reaction (PCR)-based amplification, followed by restriction fragment-length analysis. The patients were also phenotyped using dextromethorphan (DM) to determine their respective enzyme activity and assigned either a CYP2D6 EM or PM phenotype. Complete medical and treatment histories were compiled. A total of 44 patients were tested longitudinally. RESULTS: Fifty-nine patients (97%) possessed an EM genotype, consistent with previously observed distributions in demographically similar populations. In healthy seronegative populations, genotype and phenotype have been shown to be essentially interchangeable measures of CYP2D6 activity. In this cohort, 2 of the 59 patients with an EM genotype expressed a PM phenotype. In addition, 4 EM patients were less extensive DM metabolizers than any of the patients receiving medication known to inhibit CYP2D6. This apparent shift toward the PM phenotype from the EM genotype was associated with the presence of active illness. CONCLUSION: Changes may occur in HIV-positive patients such that their CYP2D6 activity approaches that of PMs, despite having an EM genotype. Neither active disease nor drug interactions alone explain the shift.

Glucuronidation and sulphation of paracetamol in HIV-positive patients and patients with AIDS.

AIMS: To gauge the effect of disease state and disease progression on the glucuronidation and sulphation of paracetamol (APAP) among HIV-positive patients and patients with AIDS. METHODS: The extent of APAP glucuronidation and APAP sulphation was assessed using a spot urine sample collected 4 h after the oral administration of 500 mg of APAP to 108 patients with AIDS or HIV infection. The molar concentrations of APAP and its glucuronide and sulphate metabolites were determined using a validated h.p.l.c. method and glucuronidation and sulphation indices were constructed using APAP metabolite/APAP molar concentration ratios. RESULTS: No effect of disease state, AIDS vs asymptomatic HIV positive vs control, on APAP glucuronidation or sulphation was observed. The patient population was studied over time and disease progression also did not significantly alter the calculated glucuronidation and sulphation indices. The effect of the concomitant administration of other therapeutic agents was assessed and in the cross sectional portion of the study dapsone appeared to significantly decrease APAP sulphation as did lamivudine. In the longitudinal portion of the study the latter effect was not observed but zidovudine was seen to increase APAP glucuronidation. The data also indicates that APAP glucuronidation may be reduced in patients who are >10% below their ideal body weight.