By J. Mannig. United States Sports Academy. 2019.

It has been accepted for many years that total protein measurement is insufficiently sensitive to detect the onset of diabetic nephropathy and that urine albumin must be used for this purpose reminyl 8mg fast delivery. This is enshrined in many clinical practice guidelines including those for type 1 and 2 diabetes produced by NICE generic reminyl 8 mg fast delivery. There is also evidence that urine albumin is a more sensitive test to enable detection of glomerular disease associated with some other systemic diseases (e purchase reminyl 8mg with mastercard. The diabetic nephropathy literature and the classification of diabetic nephropathy is based upon urine albumin excretion (commonly expressed as an ACR measurement) and the 41 Chronic kidney disease recent Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD is clear in that it requires urine albumin measurement to facilitate diagnosis of stage 1 and 2 CKD buy reminyl 4 mg on line. There is strong evidence from epidemiological studies linking urinary albumin excretion to cardiovascular mortality and kidney disease progression in people with diabetes and to cardiovascular and non-cardiovascular mortality in those without diabetes. The NKF-KDOQI guidelines therefore recommend urinary albumin measurement in preference to total protein when detecting and monitoring proteinuria. Conversely, the UK CKD guidelines and CARI guidelines have recommended urine PCR for non-diabetic kidney disease, with ACR being reserved for patients with diabetes. Increasingly the management of CKD is being undertaken by general practitioners and other non-nephrologists. Also, where the National Vascular Screening Programme identifies people with conditions such as hypertension, diabetes and impaired GFR an ACR will be recommended. Furthermore, the Quality and Outcomes framework now includes proteinuria in the CKD indicators. There is a need for consistency between detection of proteinuria in diabetes and detection of proteinuria in CKD. The current dual system of proteinuria/albuminuria reporting is at the least confusing and to patients probably unfathomable. Problems remain in defining conversion factors that would enable the proteinuria evidence base to be interpreted on the basis of urine albumin results. This is particularly true at lower levels of protein excretion, where the contribution of albumin to total protein is more variable. To attempt to address this, a call for evidence1 was circulated to registered stakeholder organisations specifically seeking evidence relating to the equivalence of ACR to PCR and to 24-hour urinary protein excretion. Instead, studies were selected that compared ACR or PCR to the reference standard test, timed overnight 42 4 Investigation of CKD or 24-hour urinary albumin (or protein) excretion. Studies were excluded if the sample size was small (lower than 100) or if the sulfosalicylic acid test, protein heat coagulation test, or urine electrophoresis were used as the reference test. Two studies compared PCR in a spot urine sample to timed urinary 24-hour protein excretion in diabetic adults98 or in non-diabetic adults with proteinuria and CKD. Six studies compared the ACR in a spot urine sample to timed overnight or 24-hour urinary albumin excretion in diabetic adults,100–103 in a Dutch general population,104 and in a South Asian general population in Pakistan. Four of these studies were relevant and admissible under the NICE Guidelines Manual. In a cross-sectional study of people aged 25 years and older in Australia (AusDiab, N=10596), both urine albumin (rate nephrelometry) and urine protein (pyrogallol red molybdate) were measured in random urine samples and the correlation between ACR and PCR was determined. The sensitivity, specificity, positive and negative predictive values of an ACR ≥30 mg/g to detect a PCR ≥0. All analyses in this paper were weighted to represent the non-institutionalised Australian population. Specifically, the correlation between urinary albumin concentration (mg/l, immuno- turbidometric assay) and urinary total protein concentration (mg/l, Ponceau S assay) was assessed in 235 timed 24-hour urine samples. Given that this manuscript was shared with the GDG as unpublished work in progress, there are some methodological limitations. The correlation between ACR (immuno- turbidometric assay) and PCR (pyrogallol red or subsequently a benzethonium turbidometric assay) was assessed. The relationships between 24-h protein excretion and ACR or PCR were also analysed in a non-randomised subgroup for whom 24-hour protein had been collected (N=1739). Areas under the receiver-operator curves were determined, along with the thresholds of both ACR and PCR to detect a 24-hour protein excretion rate >1 g/day or >450 mg/day with sensitivity of 0. This correlation significantly decreased in adults with normal ACR (<30 µg/mg) (r=0. In the figures given below, sensitivity is the proportion of people with an albumin excretion rate >30 µg/min correctly identified by the ACR test. Specificity is the proportion of people with an albumin excretion rate <30 µg/min correctly excluded by the ACR test. The specificity was high (97% in men and 95% in women). The NPV for albuminuria in those with high ACR (≥30 mg/g) was 95%. There was poor correlation between ACR and PCR in the range of 10–100 mg/mmol, and this remained the case when the analysis was restricted to subgroups (by gender, primary glomerular disease, diabetic nephropathy, and various bands of eGFR). The ratio of urine albumin to total protein significantly increased with increasing degrees of proteinuria from 0. However, there was increased scatter of ACR (below the line of unity) at lower levels of PCR. However, among people with known renal disease, total protein measures may provide better diagnostic/prognostic information (as among people with proteinuria, 9% tested negative for albuminuria). ACR had considerable scatter around a urinary protein of 300–1000 mg/day. Similarly, to predict a 24-hour urine protein >450 mg/day, a PCR threshold of 45 mg/mmol had the desired sensitivity of 0. Confidence intervals are not given for these estimates, and it is not possible to construct them from the details available. Albumin concentration was <100 mg/l and in most cases it was <20 mg/l in samples that tested negative for protein by salicylsulphonic acid precipitation. For samples with total protein in the range 0–3000 mg/l (N=116), the correlation between AER and TPER (r=0. Further, the objective of these tests in clinical practice is to detect people with CKD at increased risk of progression, and it is not yet established whether either one of proteinuria or albuminuria is superior to the other in this regard. The evidence reviewed for the measurement of protein, albumin, PCR and ACR came from different disease groups, and in some cases different ethnic groups. The GDG noted that the influence of either disease or ethnicity on actual measurement was questionable. ACR and PCR overcome inaccuracies related to timing of collection and incomplete urine collection but measure different proteins. For the identification of proteinuria in routine clinical practise a single test has been recommended. The amount of albuminuria was considered the most relevant measurement and has the advantage that the amount of albumin can be accurately measured if an immunologic assay is used. The cost-effectiveness analysis (Appendix C) showed that ACR (performed in a hospital laboratory) was more cost-effective than the use of protein or albumin reagent strips. In a sensitivity analysis, we found that ACR has to be only very slightly more accurate than PCR for ACR to be cost-effective across a range of plausible cost differentials. It is not possible to derive a simple correction factor that allows the conversion of ACR values to PCR or 24-hour urinary protein excretion rates because the relative amounts of albumin and other proteins will vary depending on the clinical circumstances; however, the GDG produced a table of approximate equivalents that will allow clinicians unfamiliar with ACR values to see the approximate equivalent PCR and 24-hour urinary protein excretion rates (Table 4.

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Some of the prerequisites for the implementation of ultrasounds in regional anesthesia include excellent understanding and knowledge of human anatomy order reminyl 4 mg without prescription, understanding of the principles related to ultrasound-guided blocks generic reminyl 8 mg without prescription, having good hand skills and hand–eye coordination (Gonano 2009) cheap reminyl 4mg line. Most ultrasound novices have problems with exact coordination between ultrasound transducer position and needle tip visualization during advancement cheap reminyl 4mg without a prescription. The American and European Societies of Regional Anesthesia (ASRA and ESRA) have recently published guidelines for training in ultrasound-guided regional anesthesia, highlighting the encouragement of individual institutions to support a quality-improvement process (Sites 2007, Sites 2009). Recently a Cochrane review reported that in experienced hands, ultrasound guidance for peripheral nerve blocks has success rates at least as peripheral nerve stimulation. The incidence of vascular puncture or hematoma formation was reduced in some studies. Ultrasounds may improve the quality of sensory and motor block. Many studies assessed block performance time and found a significant reduction with ultrasounds use. No study has assessed trunk blocks and statistical analysis was not possible due to the heterogeneity of the studies. However, the findings are likely to reflect the use of ultrasounds in experienced hands and may not be reproducible by less skilled practitioners (Walker 2009). In conclusion, the use of ultrasounds may provide a potential standard in regional anesthesia if a responsible, scientific, 34 | Ultrasound Blocks for the Anterior Abdominal Wall structured and careful implementation of such techniques is performed (Marhofer 2010). Transverse Abdominal Plexus Block Zhirajr Mokini The block of transverse abdominal plexus (TAPB) provides effective analgesia when used as a part of multimodal analgesic strategies for abdominal surgery and in chronic pain. From the first description, several clinical trials have evaluated the TAPB for postoperative analgesia in a variety of procedures (Rafi 2001) Conceptually the TAPB is a compartmental block because the local anesthetic is deposited into the fascial plane between the internal oblique muscle and the transverse abdominal muscle. Cadaveric and radiological studies have demonstrated the deposition of the local anesthetic in the TAM plane (McDonnell 2007). Unlike the rectus sheath block (RSB), which targets only the midline, the TAPB targets the entire anterior-lateral abdominal wall (Rozen 2008). The extent of the block will depend on the puncture site and the volume of local anesthetic. The typical volume used for the TAPB is 20 to 30 ml each side. The maximum block extent is observed after 30 to 60 minutes and residual block may persist after 24 hours (Lee 2008). The block can be achieved both blindly and with the use of ultrasounds. Technical aspects of the TAPB and other blocks are showed in Table 6. Blind Transverse Abdominal Plexus Block Multiple landmarks for accessing the TAM plane have been described: 1- percutaneous loss-of-resistance technique injection through the lower lumbar triangle of Jean-Louis Petit (Rafi 2001), 2- the injection between costal margin and the iliac crest at the mid-axillary line, 3- subcostal injection under the costal margin. The landmark-based techniques rely on a two pop feeling. The first “pop”,“click”, “ping” or “ting” occurs when the needle pierces the fascia between the EOM and the IOM. The second occurs when the needle pierces the fascia between the IOM and the TAM. The inferior lumbar triangle is a triangular area of the dorsal abdominal wall bordered inferiorly by the iliac crest, posteriorly by the anterior edge of the latissimus dorsal muscle and anteriorly by the posterior edge of the EOM (Figure 3. The floor of the triangle from superficial to deep is formed by the IOM and the TAM. When the triangle of Jean-Louis Petit is used as a landmark, only the fascia between the IOM and the TAM will be felt in most cases. At this level, the T6 to L1 afferent nerves are found in the compartment between the IOM and the TAM. Caudal and cephalic spread of local anesthetic occurs when it is injected into this compartment. However, the triangle of Petit can be difficult to palpate especially in obese persons or children and therefore is of limited use. Since it is found posteriorly, the block through the lumbar triangle is less convenient to perform in supine patients. It varies greatly in its position and its size is relatively small 3. Transverse Abdominal Plexus Block | 37 (Jankovic 2009). The presence of adipose tissue also changes the position significantly. As a result, it is difficult to find the triangle solely on palpation. Moreover, the lumbar triangle may frequently contain small branches of the subcostal arteries (Jankovic 2009). Finally, unexpected lumbar hernias may be found in 1% of patients (Burt 2004). Ultrasound-guided Transverse Abdominal Plexus Block Ultrasounds can overcome the problem of impalpable muscle landmarks because they allow real-time visualization of tissues, of the needle and of the spread of the local anesthetic (Figure 3. Preoperative block administration is recommended as tissue visualization with ultrasounds may be impaired after surgery and tissue manipulation. Moreover, late persistence of elevated local anesthetic levels in the plasma after abdominal blocks have been shown. A traditional or classical TAPB may be performed by injecting the local anesthetic between costal margin and iliac crest at the mid-axillary or at the anterior axillary line (Figure 3. When the transducer is positioned between costal margin and iliac crest at the mid-axillary or the anterior axillary line, the three muscular layers of the abdominal wall will be seen on the screen (Figure 3. The EOM, IOM and the TAM are seen as hypo-echoic longitudinal bands (Figure 3. Muscular fascias between the muscles are seen as hyper-echoic and hyper-lucent. The needle is inserted and advanced obliquely with an in-plane approach, parallel and aligned to the long axis of the transducer. The in-plane approach would possibly decrease the risk of advancing the needle into the peritoneal cavity. The presence of blood vessels must be always checked on the screen. Aspiration before injection is necessary to avoid intravascular placement. When the fascia between the IOM and the TAM is reached with the needle, a small volume of local anesthetic may be injected.

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This was mediated at least in part of basolateral amygdala (BLA) neuronal responses 4 mg reminyl otc. The PFC pro- via an alteration in potassium conductances reminyl 4mg line. By increasing vides a direct drive of BLA projection neurons and interneurons best 8 mg reminyl, the low threshold spike order reminyl 4 mg, DA was found to facilitate oscilla- whereas inputs from the sensory association cortex project only to the output neurons. As a result, the PFC inhibits the ability tory activity within the MD, which would potently impact of the sensory association cortex to activate BLA neuron firing. However, the PFC inputs are attenuated by elevated DA levels in the BLA, removing a source of inhibition on BLA projection neurons. Furthermore, elevated DA levels in the BLA increase the input resistance of BLA projection neurons, leading to augmenta- Basolateral Amygdala tion of nonsuppressed inputs to BLA neurons. Thus, DA receptor activation enables sensory-driven amygdala-mediated affective The basolateral nucleus of the amygdala (BLA) exhibits a responses by removal of regulatory inputs and augmenting sen- substantial innervation from the midbrain DA neurons. Locally Overall, studies support the suggestion that DA actions evoked IPSCs in neurons of the substantia nigra zona reticu- in the PFC may have a greater involvement in the regulation lata (ZR) are GABAergic in nature, and are believed to arise of novel circumstances, with the striatum involved more in from striatal afferents. These IPSCs are depressed by DA expression of learned behaviors (140). This model is consis- acting on D1 but not D2 receptors. The fact that this tent with the physiologic studies cited that show that DA depression was accompanied by increased paired-pulse facil- can selectively activate circuits within frontal cortex and itation and not by a change in membrane potential or con- striatal complex, potentially facilitating information flow ductance indicates that the effect is likely presynaptic in along new pathways when a change occurs, but playing less origin (130). It is interesting to note that the striatonigral of a role once a new stable steady state is achieved at which neurons that exhibit terminal D1 receptors do not exhibit the internal representation is at equilibrium with the pre- D1 receptors on their local collaterals within the striatum dicted external events. This suggests that these neurons can selectively traffic presynaptic receptors to long projection sites. SUMMARY OF DA ACTIONS BEHAVIORAL CORRELATES OF DA SYSTEM FUNCTION It is clear from the preceding that DA exerts multiple actions at each level of integration within the cortico-striato-pal- DA is known to play an important role in working memory lido-thalamo-cortical loop. The actions exerted at each stage and response sequencing in the PFC. In particular, DA act- of this loop appear to have marked differences, however. Within the stria- mance, whereas impairing performance in rats that had tum, DA exerts actions on presynaptic terminals containing higher baseline attentional skills (131). This is consistent glutamate, as well as affecting the actions of glutamate on with studies suggesting that optimal DA levels are required to maintain function in the PFC, with both too high or postsynaptic neurons. Combined with the reciprocal feed- low D1 stimulation leading to impaired working memory back interactions between glutamate and DA terminals, this function (132,133). Moreover, the effects of DA on cellular coupling ever, it is becoming evident that DA is not the reward signal provide a type of reversible hardwiring, which may facilitate per se, but instead is necessary for the acquisition of reinforc- performance of well-learned motor actions (141). In some cases, DA has been described as a type the VP and MD, DA has effects that would alter the behav- of error signal (136), in which the predicted occurrence ioral output by changing the state of neuronal activity of reward does not correlate with the behavioral response within these structures. Therefore, DA could enable multi- emitted to generate this reward. Thus, when a task is well ple state transitions within these regions, selecting among learned, DA neuron firing no longer is a necessary correlate competing inputs, facilitating information transfer, and al- of the reward signal. But if reward is absent, DA neuron tering states that would ultimately feed back via the thala- firing appears to decrease (137). Studies of DA overflow in mus to reinforce cortical activity that is most pertinent to the nucleus accumbens show that DA is released when the the task at hand (58,141). However, when The actions of DA may best be described not in terms the stimulation is contingent on a bar press by the rat, the of inhibition or excitation, but rather as related to the gating DA overflow does not occur even in the presence of the of inputs and modulation of states of neuronal elements. These data suggest that the lack This modulation of information integration is then further of DA system activation during a well-learned contingent influenced at the network level via the actions of DA on reinforcement task is not simply a failure to activate DA interneurons or cell coupling. Such a description is consis- neuron firing, but instead may represent an offsetting inhib- tent with the behavioral actions of this transmitter as well, itory influence over the DA system, either at the level of in that it does not directly produce a motor output or reward the DA cell body or the terminal. Indeed, the reports of an signal, but instead modulates inputs and adjusts the states anticipatory increase in extracellular DA in the accumbens of the organism in order to redirect the stimulus-response prior to self-administration of a DA drug such as cocaine output to achieve the most effective behavioral strategy. Presynaptic muscarinic (M3) receptors reduce excitatory transmission in dopamine neu- rons of the rat mesencephalon. Grace has received research support from Pharmacia- 565. Upjohn and Warner-Lambert/Parke Davis, as well as travel 18. Keefe KA, Zigmond MJ, Abercrombie, ED Extracellular dopa- support for presenters at a scientific panel he co-organized mine in striatum: influence of nerve impulse activity in medial for Pharmacia-Upjohn. Burst stimulation REFERENCES of the medial forebrain bundle selectively increase Fos-like im- munoreactivity in the limbic forebrain of the rat. Morphology and electrophysiological prop- burst stimulation of the medial forebrain bundle. Eur J Neurosci erties of immunocytochemically identified rat dopamine neu- 1997;9:2370–2382. The control of firing pattern in nigral pedunculopontine tegmental nucleus in the rat produces burst dopamine neurons: single spike firing. J Neurosci 1984;4: firing in A9 dopaminergic neurons. Role of the subthalamic nucleus in the repeated L-DOPA administration to dopamine-depleted rats: regulation of nigral dopamine neuron activity. Synapse 1992; its potential role in mediating the therapeutic response to L- 12:287–303. Effects of haloperidol on the activity and of dopamine neuron firing patterns. Curr Opin Neurobiol 1999; membrane physiology of substantia nigra dopamine neurons 9:690–697. Loss of autoreceptor bursting activity in nigral dopamine-containing neurons. Brain function in dopaminergic neurons from dopamine D2 receptor Res 1999;817:104–109. Monoamine oxidase cortex in the rat induces patterns of activity in midbrain dopami- inhibition causes a long-term prolongation of the dopamine- nergic neurons, which resemble natural burst events. Synapse induced responses in rat midbrain dopaminergic cells. N-methyl-D-aspartate re- the rat prefrontal cortex synapse on pyramidal cells that pro- ceptors mediate a slow excitatory postsynaptic potential in the ject to the nucleus accumbens. J Neurosci 1999;19:11049– rat midbrain dopaminergic neurons.

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Samples were centrifuged discount 4 mg reminyl, and the The relative EEG beta amplitudes (beta divided by total generic 4 mg reminyl visa, plasma separated and frozen until the time of assay buy reminyl 4mg on-line. The expressed as percent) in the predose recordings were used as the baseline generic 8mg reminyl amex. All values after lorazepam administration were expressed as the increment or decrement over the mean predose baseline value, with values averaged across eight recording sites. The EEG change values were subsequently used as pharmacodynamic effect (E) measures in kinetic- dynamic modeling procedures described below. For phar- macokinetic modeling, the relation of plasma lorazepam concentration (C) to time (t) was assumed to be consistent with a two-compartment model (Figs. Examination of plots of pharmacodynamic EEG effect versus plasma lorazepam concentration (E vs. C) indicated counterclockwise hysteresis (see below), suggesting a delay in equilibration of lorazepam between plasma and the site of pharmacodynamic action in brain. This equilibration ef- fect has been described in previous clinical and experimental studies of lorazepam (34,36–39). Three mathematical relationships between con- centration (C) and change in pharmacodynamic effect (E) that are ship was modified to incorporate a distinct 'effect site,' at commonly applied in kinetic-dynamic modeling procedures. For which the hypothetical lorazepam concentration is CE(Fig. The apparent rate constant for drug disappearance fect, EC50 is the concentration producing a value of E equal to 50% of E , and A is an exponent. For the exponential and linear from the effect compartment is kEO; this rate constant deter- max models, m is a slope factor. Under these assumptions, the relation of E to CE was postulated to be consistent with a sigmoid Emax model (Fig. Results Kinetic variables for lorazepam were similar to those re- ported in previous single-dose studies of lorazepam pharma- cokinetics (34,40–45). The bolus-infusion scheme rap- idly produced mean plasma lorazepam concentrations in the range of 18 to 19 ng/mL, values close to the mean predicted value of 24 ng/mL. Schematic representation of the kinetic-dynamic Lorazepam infusion produced significant increases in model for the lorazepam study. Intravenous lorazepam was as- EEG beta amplitude throughout the 24-hour duration of sumed to have kinetic behavior consistent with a two-compart- ment model: reversible distribution to a peripheral compartment, the study. The maximum change over baseline was mea- and first-order elimination (clearance) from the central compart- sured at 0. Lorazepam in plasma was postulated to dosage, whereas the maximum plasma concentration was equilibrate with a hypothetical effect site, from which the exit rate constant is KEO. Finally, effect-site concentrations were pre- measured immediately after the loading dose (Fig. Implications Maximum EEG effects of lorazepam were significantly de- layed following the initial intravenous bolus dose. Previous single-dose pharmacodynamic studies of lorazepam, using the EEG or other methods for quantitation of benzodiaze- FIGURE 38. Plasma lorazepam concentrations (solid circles) to- gether with the pharmacokinetic function determined by nonlin- FIGURE 38. Mean values of plasma lorazepam concentration, ear regression (solid line), in a representative volunteer subject. Shown are the derived pharmacokinetic variables of elimination Note that pharmacodynamic EEG effects are delayed following half-life (t1/2), volume of distribution (Vd), and clearance (CL). Left: Mean values of plasma lorazepam concentration versus pharmacodynamic EEG effect at corresponding times, with arrows indicating the direction of increasing time. The data points (closed triangles) are the hypothetical effect site concentrations and pharmacodynamic effect values at corresponding times. The solid line is the link model function determined by nonlinear regression,yielding the indicated valuesof EmaxandEC50. For the CYP isoforms nous dosage, for example, maximum effects may be delayed most relevant to human drug metabolism, each has its own for an average of 30 minutes after dosage. Experimental distinct pattern of relative abundance, anatomic location, studies of the time-course of whole-brain concentrations mechanism of regulation, substrate specificity, and suscepti- of lorazepam, or of the degree of benzodiazepine receptor bility to inhibition and induction by other drugs or foreign occupancy, indicate that the delay is attributable to the slow chemicals (Table 38. The expression and in vivo function physical entry of lorazepam into brain tissue, probably be- of at least two CYP isoforms (CYP2D6 and CYP2C19) cause of the relatively low lipid solubility of lorazepam (34, are regulated by a genetic polymorphism, such that some 38,39). The delay was mathematically consistent with a ki- members of a population fail to express 'normal' levels netic-dynamic model incorporating a hypothetical 'effect of enzyme or expresses poorly functional protein (56–62). The half-life Individuals identified as 'CYP2D6 poor metabolizers,' as for equilibration between plasma and the effect compart- an example, have very low clearance of drugs that are major ment was approximately 9 minutes. This matches clinical substrates for biotransformation by CYP2D6 (such as desi- experience indicating that intravenous lorazepam cannot pramine, nortriptyline, venlafaxine, tramadol, and dextro- easily be used in situations requiring minute-to-minute ti- methorphan). Such individuals are at risk for developing tration of sedative or amnestic effects (40). Nonetheless, high and potentially toxic plasma concentrations of these intravenous lorazepam can be used for the treatment of sta- tus epilepticus, although its onset of action may be some- what slower than that of intravenous diazepam (46,47). CYTOCHROMES P-450 IN PSYCHOPHARMACOLOGY: THE IMPORTANCE OF P-450-3A ISOFORMS FIGURE 38. Nomenclature system for the cytochrome P-450 (CYP)superfamily ofenzymes. Following theCYP designation,the The cytochrome P-450 (CYP) superfamily of drug metabo- number-letter-number sequence indicates the family, subfamily, lizing enzymes is now established as being of primary impor- and specific isoform. OVERVIEW OF HUMAN CYTOCHROMES P-450 Relative Hepatic Genetic CYP Isoform Abundance Polymorphism Representative Substrates 1A2 13%? Caffeine, theophylline, tacrine 2B6 <1% − Bupropion, propofol 2C9 15% + S-warfarin, phenytoin, tolbutamide, NSAIDs 2C19 4% + S-mephenytoin, omeprazole (partial contributor to many others) 2D6 2% + Some psychotropic and cardiac drugs 2E1 7% − Chlorzoxazone, some inhaled anesthetics 3A4/5 29%a − Many (see also Table 38. It is not established to what extent hepatic CYP3A5 is of clinical significance for drug-metabolizing The CYP3A Isoforms activity. The location and sequence of the genetic element responsible The overall importance of the CYP3A subfamily of drug- metabolizing enzymes, particularly in the field of psycho- for CYP3A4 expression have been identified, as well as a pharmacology, has become increasingly evident over the last regulatory segment located on the 5′ flanking region corre- decade (6–9,63–69) (Table 38. Its high substrate capacity is a consequence of liver (70) (Table 38. Within the CYP3A subfamily, both the relatively high value of maximum reaction velocity CYP3A4 is the most important in the adult human, in terms (Vmax, expressed in nanomoles of product produced per unit of drug-metabolizing activity as well as quantitative domi- time per milligram of protein) in a Michaelis-Menten rela- nance. CYP3A5, another CYP3A isoform, is also detected tionship, as well as the high quantitative abundance of the protein in hepatic tissue. The low-affinity characteristic is reflected in the high Km value (substrate concentration cor- responding to 50% of Vmax) in a Michaelis-Menten relation- TABLE 38. One consequence is that CYP3A-mediated metabo- FOR HUMAN CYP3A lism usually is not 'saturable' at substrate concentrations within the therapeutic range, because this range is likely to Contribution of CYP3A to Net Clearance be far below the reaction Km.

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