Assessment of drug metabolism in hepatic disease: Comparison of plasma kinetics of oral cyclobarbital and the intravenous aminopyrine breath test

Summary The exhalation of ¹⁴CO₂ derived from an i.v. tracer dose of [dimethylamine-¹⁴C]aminopyrine has been investigated in normal controls and patients. They subsequently ingested 200 mg cyclobarbital calcium in the evening and the decline in the plasma drug level over the following 2 days was measured by thin-layer chromatography. The peak specific activity of exhaled ¹⁴CO₂ occurred 0.5–2 h after ¹⁴C-aminopyrine injection in the absence of liver disease and in non-cirrhotic liver disorders. It was delayed in certain patients with cirrhosis. Compared to 8 medically healthy subjects, 10 patients with acute viral hepatitis, 8 with cirrhosis and 10 with fatty liver exhibited a significantly increased half-life of ¹⁴CO₂ exhalation. Normal mean values were found in 12 patients with non-cirrhotic alcoholic liver disease and in 14 patients with non-hepatic diseases. The cyclobarbital (CB) half-life was prolonged and the clearance reduced in patients with viral hepatitis, cirrhosis, or alcoholic liver damage as compared to data from 17 control subjects. Due to a larger apparent volume of distribution, patients with fatty liver disease had an increased CB half-life, although its clearance was normal. A close negative correlation was detected between the clearance and the logarithm of the CB level measured 36 h after drug ingestion. The oral CB test evaluated from a single blood sample taken about 36 h after drug administration appears to be a useful indicator of human drug metabolising capacity. Discrimination between patients with and without disordered liver function was similar in the two drug elimination tests.     

Lack of interference by sorbitol with aminopyrine breath test

Summary The effect of sorbitol on the aminopyrine breath test was investigated in 13 patients with various liver diseases given a bolus dose of sorbitol 20 mg · kg^–1 i. v. 30 min after ¹⁴C-aminopyrine and 13 patients without the sorbitol bolus who also underwent an aminopyrine breath test.The time course of ¹⁴CO₂ exhalation after the bolus of sorbitol did not differ from that in the control group.     

Drug pharmacokinetics and the carbon dioxide breath test

The interrelationship of the pharmacokinetics of a drug and the expiration of carbon dioxide formed as a metabolite have been studied. The pharmacokinetic characteristics of the drug that affect the usefulness of the carbon dioxide excretion as a measure of liver function were examined by means of computer simulations. The parent drug extraction ratio, fraction demethylated, volume of distribution, and absorption rate of an oral dosage form all contribute to the carbon dioxide breath test result. A drug that would be a useful substrate when the carbon dioxide breath test is used as a probe for changes in liver function should be at least 50% metabolized by demethylation, have a hepatic extraction ratio of 0.2–0.5, and be administered in a form that is rapidly absorbed.Appendix b. symbols CL _c net clearance of formaldehyde to carbon dioxide - CL _int,f intrinsic hepatic clearance of formation of formaldehyde from parent drug (bound and unbound to plasma proteins) - CL _int,p intrinsic hepatic clearance of total parent drug (bound and unbound to plasma proteins) - CL _sys,f systemic hepatic clearance of formation of formaldehyde from parent drug,Q _H CL _int,f /(Q _H +CL _int,p ) - CL _sys,p systemic hepatic clearance of parent drug,Q _H CL _int,p /(Q _H +CL _int,p ) - E extraction ratio,CL _int,p /(Q _H +CL _int,p - F I-E fraction escaping first-pass metabolism,Q _H/(Q _H +CL _int,p - fm fraction of parent drug metabolized by demethylation to formaldehyde,CL _int,f /CL _int,p - HCHO amount of formaldehyde - [HCHO] concentration of formaldehyde - _a absorption rate constant - M _i metabolite of P formed by routes other than demethylation - M ₁ metabolite of P formed by demethylation - P amount of parent drug in the body - [P] concentration of parent drug measured in arterial blood - P _A amount of parent drug at absorption site - P _L amount of parent drug in the liver - Q _H hepatic blood flow - V _F volume of distribution of formaldehyde - V _p volume of distribution of parent drug     

儿童使用氨基比林发生药品不良反应及不良事件文献分析

目的 系统评价儿童使用氨基比林不同制剂发生药品不良反应（ADR）或药品不良事件（ADE）在人体器官、严重程度的分布、构成及影响因素。方法 在知网、维普、万方、中国生物医学文献数据库、Pubmed、Embase中检索,检索词为氨基比林、安乃近、去痛片等,加不良反应、不良事件、过敏等自由词进行综合检索。按纳入与排除标准选择文献、提取数据,并按不同类别（年龄、过敏史、涉及系统、联合用药等）统计发生在胎儿期至青春期的儿童使用氨基比林不良反应发生总数、构成比。结果 ①共纳入中文文献484篇,包括个病例,其中发生在儿童的有20例。②共纳入英文献70篇,包括73个病例,其中发生在儿童的有34例。③中、英文报道的药品不良反应/事件主要涉及血液系统、皮肤黏膜系统、泌尿系统、循环系统导致发生休克等全身反应;预后各不相同,有174例痊愈（72.80%）,30例死亡（12.%）,还有14例（.86%）的结局分别为骨髓移植、指及趾截肢、胃大部切除等严重ADR;另有21例（8.79%）预后不详。④多数ADR的用药剂量为常规剂量,但也有医务人员超剂量给药引起的ADE。结论 使用氨基比林可能引起儿童造血系统、泌尿系统等严重伤害,每年都有较多严重ADR甚至死亡案例报道。应尽快淘汰氨基比林这个可能给儿童带来致死毒性的药物。     

First pass hydroxylation of nortriptyline: Concentrations of parent drug and major metabolites in plasma

Summary Nortriptyline was given orally and intramuscularly to six depressed patients. Plasma concentrations of parent drug and the unconjugated and conjugated principal metabolite, 10-hydroxynortriptyline, were determined by mass fragmentography. There was a significant decrease in the area under the nortriptyline plasma concentration — time curve after the oral route of administration, whilst the elimination rate was unchanged. With the oral dose, plasma concentrations of the metabolites were higher and peaked earlier than after intramuscular administration, whilst the opposite was true for the parent compound. This proves that the difference in bioavailability between the two routes of administration was due to first pass metabolism. As determined from the ratio between corresponding areas, the relative bioavailability of the oral dose was 66±21 S.D. per cent. This fraction is higher than that reported previously when intravenous nortriptyline was used as the reference dosage form.     

Plasma and cerebrospinal fluid concentrations of temazepam following oral drug administration

Summary Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media.The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.     

LC/APCI/MS在血药浓度研究中的应用

目的：建立可用于血样检测的小分子药物代谢分析的高灵敏、简捷的液相色谱/大气压解离质谱联用(LC/APCI／MS)方法。方法：海洛因、6—乙酰吗啡、乙酰可待因和螺内酯分别于大鼠血浆中39℃孵育，定时取样，用LC/APCI／MS测定原药及代谢产物的浓度，绘制代谢曲线。结果：海洛因在5min内消失，经6—乙酞吗啡最终代谢为吗啡，30min后吗啡浓度达到峰值；6—乙酰吗啡在20min内消失，代谢产物吗啡的浓度随之达到峰值；乙酞可待因在血浆中代谢缓慢，60min后仅有部分代谢，生成可待因；螺内酯也以缓慢的速度代谢，60min后代谢产物坎利酮的浓度尚远离峰值。结论：LC/APCI／MS作为高灵敏废的简捷方法用于血药浓度研究具有广阔前景。     

Plasma levels and myocardial content of verapamil,norverapamil and two N-dealkyl-metabolites in man

Summary The plasma levels and myocardial content of verapamil and its metabolites norverapamil, N-dealkylverapamil and N-dealkylnorverapamil were determined in 15 patients with valvular [3] or ischaemic [12] heart disease. The mean myocardial plasma concentration ratio (M/P) was 7.05 for verapamil, 11.45 for norverapamil, 8.93 for N-dealkylverapamil, and 11.33 for N-dealkylnorverapamil, with great interpatient variability. The highest M/P ratios of verapamil were generally found in patients with the lowest plasma levels, suggesting that saturable tissue uptake may occur.     

Dose dependence of the14C-aminopyrine breath test

Summary Although the aminopyrine breath test has received much attention, the question has not yet been settled whether pharmacological or tracer doses of the drug should be used. Nine volunteers were given¹⁴C-aminopyrine 9 mg/kg or a tracer amount, in a randomized sequence and according to a crossover design. The specific activity of¹⁴CO₂ in breath was significantly different only during the first hour. Up to the 8th hour the disappearance of¹⁴CO₂ from breath was smaller after the pharmacological (28.5±SD 5.4%/h) than after the tracer dose (36.2±10.6%/h; p<0.05). The overall disappearance of¹⁴C-atoms from the subjects was significantly slower after the higher dose. In view of the smaller radiation exposure and the decreased risk of agranulocytosis, the use of a tracer dose appears preferable.Supported by the Swiss National Science Foundation     

Plasma levels of parent drug and metabolites in patients receiving oral and depot fluphenazine

We evaluated the metabolism of fluphenazine (FLU) in patients treated with either the oral form of FLU or with fluphenazine decanoate (FD). Samples for both patient populations were analyzed using four different radioimmunoassays developed in our laboratories for fluphenazine, fluphenazine sulfoxide (FS), 7-hydroxy fluphenazine (7OHFLU), and fluphenazine N-oxide (FLUNO). In patients receiving oral FLU the levels of FS and 7OHFLU were significantly higher than levels of FLU. In patients receiving FD, the levels of metabolites were significantly lower than FLU levels. This supports the view that drug metabolism is likely to be a more important factor for patients treated with an oral as opposed to a depot phenothiazine neuroleptic.     

Patient age is a strong independent predictor of 13C-aminopyrine breath test results: a comparative study with histology, duplex-Doppler and a laboratory index in patients with chronic hepatitis C virus infection

1. Noninvasive tests for the staging of chronic hepatitis C virus (HCV) infection would be an attractive alternative to liver biopsy. The 13C-aminopyrine breath test (ABT) has been proposed for the noninvasive assessment of hepatic function and partly correlates with fibrosis. We aimed to investigate causes for the lack of discriminatory power for different degrees of hepatic fibrosis. 2. Eighty-three patients (median age 49 years (28-78 years)) with chronic HCV infection underwent the ABT after an oral load of 75 mg N,N-dimethyl-13C-aminopyrine. Portal vein flow was assessed by duplex-Doppler and a laboratory index (aspartate aminotransferase to platelet ratio index or APRI) was calculated. Parameters were compared with liver histology. 3. The cumulative 13C-recovery differed significantly between patients without relevant fibrosis (fibrosis score 0-2) and cirrhosis (5-6), beginning after 30 min of sampling (P < 0.05). The ABT did not discriminate patients with fibrosis scores 3-4 from the remaining two patient groups. Sensitivity and specificity for the prediction of cirrhosis was 73.4-82.8% and 63.2-68.4%, depending on the sampling time. Compared with the fibrosis score (P = 0.04), patient age was a highly significant independent predictor for the 13C-recovery (P < 0.0001). Aspartate aminotransferase to platelet ratio index and duplex-Doppler predicted cirrhosis with 76.6%vs. 87.5% sensitivity and 63.2%vs. 68.4% specificity. 4. Our data suggest an age-dependent decrease of cytochrome P450 activity which probably accounts for the large overlap of ABT results that preclude clear differentiation. This is also consistent with former pharmacodynamic trials. Age-adapted reference ranges could improve ABT results.     

Quantitation of CSF concentrations and biological activity of probenecid metabolites

Summary The concentrations of probenecid and four of its metabolites have been examined in plasma and CSF by electron capture gas chromatography after extractive methylation. The plasma concentration of each of the metabolites was in the range 1,5–15 µg/ml and constituted less than 10% of the parent compound. The penetration into CSF of the metabolites was lower than that of probenecid. The concentration of each of the metabolites was below 0,2 µg/ml and the total concentration never exceeded 10% of the probenecid concentration. The inhibitory effect of the metabolites on uptake was tested in rabbit renal cortex using³H-p-amino-hippuric acid. The inhibitory effect was low. From the low activity and relatively low concentrations of the metabolites in CSF it is concluded that probenecid metabolites do not contribute to the probenecid-induced blocking effect of acid transport from the CSF.     

Quantitative levels of aripiprazole parent drug and metabolites in urine

Objective

The aim of this study is to assess urine levels of aripiprazole and metabolites among patients receiving steady-state dosing of aripiprazole.

Methods

One hundred fifty adults, judged compliant with a stable aripiprazole regimen, had observed dosing for 5 consecutive days. Urine specimens, obtained on days 1, 4, and 5, were analyzed for pH, creatinine, specific gravity, and for aripiprazole, OPC3373, and dehydroaripiprazole. Linear regression was used to assess the association between unadjusted urine levels of each drug/metabolite and dose taken, and linear stepwise multiple regression was performed to identify variables that added to the explanation of the variance.

Results

OPC3373 was found in 97 % of urine samples, whereas unchanged aripiprazole and dehydroaripiprazole were found in only 58 and 39 % of samples, respectively. Variance in urine metabolite levels accounted for by medication dose was relatively low for each individual drug/metabolite, r ² only 0.13 to 0.23. However, when OPC3373 was adjusted for age, weight, sex, and urine creatinine values, the r ² improved to 0.63, and further improved to 0.70, when height, urine specific gravity, and the presence of dehydroaripiprazole were added in a stepwise multiple regression model.

Conclusions

Unadjusted urine levels of aripiprazole and metabolites are not strongly related to aripiprazole dosing, however, accounting for key variables yields a strong relationship between measurable urine parameters and dose taken. By defining the expected range of adjusted urine levels for each dose, the potential exists for a clinical test to identify partially nonadherent individuals who would not have been identified by conventional “present vs. absent” urine drug testing.     

^14C呼气试验在诊断幽门螺杆菌感染中的价值

目的 :研究14C呼气试验在诊断幽门螺杆菌 (HP)感染中的价值。方法 :选择80例经胃镜活检组织病理证实的HP阳性病例作为研究对象 ,并在抗HP治疗前同步进行血清抗HP及14C呼气试验检查。结果 :在80例组织病理证实的HP阳性病例中 ,14C呼气试验阳性率为92 5 % ,血清抗HP试验阳性率为60%。14C呼气试验阳性率与组织学诊断阳性率之间差异无显著性 ,14C呼气试验阳性率与血清抗HP阳性率之间比较差异有显著性 (P<0 05)。结论 :14C呼气试验是一较理想的非侵入性诊断HP的方法     

肠易激综合征治疗前后氢呼气试验参数及胃肠激素分泌水平的变化研究

目的 探究肠易激综合征(IBS)患者治疗前后氢呼气试验参数及胃肠激素分泌水平的变化情况.方法 采用氢呼气试验测定正常对照组及IBS患者口盲传输时间(OTCC)及产生H2浓度,同时利用放射免疫法检测正常对照组及IBS患者血浆中胃动素(MTL)、血管活性肠肽(VIP)、胆囊收缩素(CCK)和生长抑素(SS)的含量.结果 治疗前腹泻组患者OCTT显著低于对照组和便秘组,且便秘组OCTT显著高于对照组(P＜0.05),治疗前IBS患者H2浓度和SIBO阳性率均显著高于对照组(P＜0.05),治疗后H2浓度和SIBO阳性率显著降低,差异有统计学意义(P＜ 0.05).治疗前腹泻组患者血浆中MTL和CCK明显高于对照组和便秘组,治疗后腹泻组患者MTL和CCK水平较治疗前显著降低,而便秘组较治疗前显著升高(P＜0.05);而治疗前IBS患者血浆中VIP和SS明显高于对照组,治疗后IBS患者VIP和SS水平较治疗前显著降低,差异有统计学意义(P＜0.05).结论 氢呼气试验参数和胃肠激素分泌水平改变与IBS发病过程密切相关.     

~(14)C—尿素呼气试验诊断幽门螺杆菌感染

目的评估14C-尿素呼气试验诊断幽门螺杆菌感染的诊断价值。方法对220例患者同步完成快速尿素酶试验、病理、14C-尿素呼气试验检查,以病理(HE染色)、快速尿素酶试验均阳性为诊断幽门螺杆菌感染的标准,评价14C-尿素呼气试验对幽门螺杆菌感染的诊断价值。结果14C-尿素呼气试验的敏感性为90%,特异性为98%,准确性为93.4%。结论14C-尿素呼气试验是幽门螺杆菌感染无创伤、敏感和特异的诊断方法。     

精神分裂症患者氯氮平血药浓度的研究

目的：探讨氯氮平血药浓度与其抗精神分裂症治疗疗效的关系。方法：抽取80例精神分裂症患者,给予氯氮平≥400mg/d治疗8周。治疗前后用简明精神病评定量表（BPRS）评定氯氮平疗效,按BPRS减分率≥20％和＜20％分为有效组和无效组。氯氮平血浆血药浓度用高效液相色谱分析法测定。结果：采用x^2检验进行分析。结果80例患者中76例完成了整个试验,其结果分析表明在氯氮平治疗第4周的血药浓度与BPRS疗效评价没有明显关系,而在治疗后第8周血药浓度＞350ng/ml治疗组疗效显著（P＜0.05)。结论：氯氮平治疗第8周血药浓度与临床疗效有明显相关性。     

Clozapine: Plasma levels and prolactin response

Serial plasma clozapine levels and serum prolactin levels were determined in two schizophrenic patients receiving clozapine, a novel antipsychotic drug. Despite marked therapeutic response and substantial clozapine blood levels, prolactin levels obtained 11–12 h after the last oral dose were unaffected or only minimally elevated. This confirms previous evidence of clozapine's unusal characteristics.     

^14C呼气试验与快速尿素酶试验检测幽门螺杆菌感染的对比研究

目的：探讨^14C呼气试验和快速尿素酶试验两种方法对幽门螺杆菌（H.pylori）感染的诊断价值。方法：107例有消化道症状的患者,分别用^14C呼气试验和快速尿素酶试验两种方法进行检测,比较两种方法对H.pylori检测符合率及灵敏度、特异度、阳性预测值和阴性预测值。结果：两种方法对H.pylori感染的检出率分别为92.0%和89.8%,但差异无统计学意义。^14C呼气试验的灵敏度、特异度、阳性预测值和阴性预测值分别为92.7%、88.0%、93.8%和84.6%。快速尿素酶试验灵敏度、特异度、阳性预测值和阴性预测值分别为87.8%、80.0%、91.1%和71.4%。结论：^14C呼气试验和快速尿素酶试验对H.pylori感染的诊断均有很高的敏感性和特异性,是临床上用于H.pylori感染诊断的可靠方法。