Macaque cytochromes P450: nomenclature, transcript, gene, genomic structure, and function

Monkeys, especially macaques, including cynomolgus (Macaca fascicularis) and rhesus monkeys (Macaca mulatta), are frequently used in drug metabolism studies due to their evolutionary closeness to humans. Recently, numerous cytochrome P450 (P450 or CYP) cDNAs have been identified and characterized in cynomolgus and rhesus monkeys and were named by the P450 Nomenclature Committee. However, recent advances in genome analysis of cynomolgus and rhesus monkeys revealed that some monkey P450s are apparently orthologous to human P450s and thus need to be renamed corresponding to their human orthologs. In this review, we focus on the P450s identified in cynomolgus and rhesus monkeys and present an overview of the identity and functional characteristics of each P450 cDNA in the CYP1-4 families. Information on the Japanese monkey (Macaca fuscata), African green monkey (Cercopithecus aethiops), and marmoset (Callithrix jacchus), primate species used in some drug metabolism studies, are also included. We compared the genomic structure of the macaque P450 genes to those of human and rat P450 genes in the CYP1-4 families. Based on sequence identity, phylogeny, and genomic organization of monkey P450s, we determined orthologous relationships of monkey P450s and, in this article, propose a revised nomenclature: CYP2B17/CYP2B30 to CYP2B6, CYP2C20/CYP2C74 to CYP2C8, CYP2C43/CYP2C83 to CYP2C9, CYP2C75 to CYP2C19, CYP2F6 to CYP2F1, CYP3A8/CYP3A21/CYP3A64 to CYP3A4, CYP3A66 to CYP3A5, and CYP4F45 to CYP4F2. The information presented in this review is expected to promote a better understanding of monkey P450 genes through comparative genomics and thereby make it more feasible to use monkeys in drug metabolism studies.     

Behavior maintained by intravenous injection of codeine,cocaine, and etorphine in the rhesus macaque and the pigtail macaque

Lever-pressing behavior of two species of macaque, the rhesus macaque (M. mulatta) and the pigtail macaque (M. nemestrina) was maintained by intravenous injection of codeine, etorphine, or cocaine. Monkeys responded under a fixed-ratio 30 timeout 600 s schedule of drug injection during two daily experimental sessions. Drug-maintained behavior was studied under two access conditions. Under the first condition, selected doses of codeine or cocaine were available for ten consecutive sessions. Under the second condition, responding was maintained by 0.32 mg/kg codeine or 0.32 mg/kg cocaine, and saline and selected doses of codeine, etorphine, and cocaine were substituted during single experimental sessions. Performance varied with drug and injection dose, access condition, and macaque species. For all three drugs, response rate increased and then decreased as injection dose increased. Maximal rates were maintained by 0.10–0.32 mg/kg codeine, 0.0003–0.001 mg/kg etorphine, and 0.10–0.32 mg/kg cocaine. A cocaine dose of 0.32 mg/kg maintained higher rates than any dose of codeine or etorphine, and maintained higher rates when available during consecutive sessions than when substituted for codeine for a single session. Codeine maintained similar rates under all access conditions. The pigtail macaques had short catheter lives, did not readily acquire codeine-maintained responding, and displayed lower rates of drug-maintained lever pressing than the rhesus macaques.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist,talsaclidine

RATIONALE: Muscarinic-acetylcholine receptor agonists are yet to be used clinically for the treatment of Alzheimer's disease (AD) even though laboratory evidence continues to support the potential for such an approach. OBJECTIVES: The purpose of this study was to evaluate the M(1)-preferring agonist talsaclidine in aged monkeys for effects on working memory. METHODS: Three doses (0.6, 1.2, and 2.4 mg/kg, PO) of talsaclidine and two time intervals (45 min and 8 h) after drug administration were evaluated in seven aged rhesus macaques trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. The relative effectiveness of talsaclidine was also compared with another M(1)-preferring agonist WAY-132983 that was previously studied in this laboratory. RESULTS: Talsaclidine improved DMTS accuracy only during sessions initiated 8 h after administration of one of the doses (i.e. 0.6 mg/kg). The drug's enhanced effectiveness at the 8-h time point relative to the 45-min time point was surprising in view of the fact that plasma concentrations were highest 45 min after administration. A higher dose of talsaclidine (4.7 mg/kg) resulted in side effects (lethargy and excessive drooling) in some animals. Individualized optimal doses of talsaclidine were associated with 7.4% and 10.6% improvement in overall (all trials averaged) DMTS accuracy during the 45 min and 8 h post-administration sessions, respectively. Under similar experimental conditions WAY-132983 increased DMTS accuracy by up to 15.6% above control levels. CONCLUSION: Both talsaclidine and WAY-132983 provide at least modest improvements in DMTS accuracy in aged monkeys at some doses; however, challenges remain regarding the achievement of an adequate level of efficacy and reliability while minimizing side effects with these compounds. The positive findings do, however, support further study of the potential use of direct muscarinic agonists in the treatment age-related disorders of memory function.     

Effects of atropine on respiratory sinus arrhythmia (RSA) in the rhesus macaque

Twelve juvenile to adult rhesus macaques were administered atropine sulfate (0, 14, 44, and 140 mcg/kg IM). The amplitude of the respiratory sinus arrhythmia (RSA) in the rhesus macaque was estimated using a Vagal Tone Monitor (VTM). The estimate of RSA (termed V; vagal tone) was significantly reduced for nearly 3 hr after all doses of atropine, suggesting possible central nervous system effects. Heart period (R-R interval) was reduced briefly after dosing. Overall heart period variability (HPV) was depressed after all doses of atropine. The amount of atropine required to decrease HPV and V by 30% was similar to that reported for the human. The rhesus monkey was determined to have little resting vagal tone as estimated by V. A large slow wave oscillation contributed to the overall variability in heart period. It is concluded that the rhesus monkey exhibits a similar sensitivity to atropine as did the human and, therefore, provides a useful model for the study of cholinergic drug actions and their effects on RSA.     

Acute effects of d-amphetamine in a monkey operant behavioral test battery

The acute effects of d-amphetamine were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching-to-sample (DMTS, n = 6), conditioned position responding (CPR, n = 7), progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tasks. Performance in these tasks is thought to depend upon specific brain functions such as short-term memory and attention (DMTS), color and position discrimination (CPR), motivation to work for food (PR), time perception (TRD), and learning (IRA). d-Amphetamine sulfate (0.01-1.0 mg/kg IV), given 15-min pression produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses of 0.3 and 1.0 mg/kg for TRD and at 1.0 mg/kg for CPR when compared to saline injections. Accuracy was not consistently affected in the DMTS or IRA tasks. Response rates decreased or response latencies increased significantly at doses of 0.3 and 1.0 mg/kg in the PR and DMTS tasks. A dose of 0.1 mg/kg for the IRA and TRD tasks, 0.3 mg/kg for DMTS and 1.0 mg/kg for the CPR tasks significantly decreased percent task completed. Thus, the relative sensitivities of these tasks for detecting d-amphetamine behavioral effects were IRA = TRD greater than PR = DMTS greater than CPR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Self-administration of an enkephalin analog by rhesus monkey.

Intravenous injections of a synthetic enkephalin analog, FK-33-824 were found to maintain operant responding under second-order schedule control (FR 4[VR 16:S]) in five, morphine-dependent rhesus monkeys. All monkeys self-administered enkephalin in amounts equivalent to morphine at comparable doses per injection. Each of five doses of enkephalin (0.5, 0.25, 0.125, 0.05 and 0.01 mg/kg/inj) were substituted for morphine during 10 consecutive sessions over a 56 hr period. No monkey developed opiate withdrawal signs during enkephalin substitution except at the lowest enkephalin dose (0.01 mg/kg/inj). Although the number of enkephalin injections self-administered increased as the dose per injection progressively decreased, there was a significant linear decrease (p less than 0.05) in mg/kg/enkephalin per session at doses of 0.25 mg/kg/inj and below. Reductions in morphine dose per injection, over a range of 0.5 to 0.125 mg/kg/inj produced comparable increases in number of injections per session, but no significant changes in morphine intake. The number of food pellets earned on a second order FR 4 (VR 16:S) schedule decreased during enkephalin substitution. These decreases were significant at the highest doses of enkephalin (0.5 to 0.125 mg/kg/inj). These data attest to the reinforcing characteristics of an enkephalin analog in rhesus monkey and suggest that natural polypeptides may contribute to the reinforcing properties of opiate drugs.     

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey. 2. After a single oral dosing of 14C-I (10 mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 +/- 0.3% in rat, 46.9 +/- 1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey. 3. After a single i.v. dose of 14C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71 +/- 0.01 to 0.93 +/- 0.05 as the dose was increased from 0.2 to 20 mg/kg.     

Diclofenac hydroxylation in monkeys: efficiency, regioselectivity, and response to inhibitors

The catalytic efficiency, regioselectivity, and response to chemical inhibitors of diclofenac (DF) hydroxylation in three Old World monkey liver microsomes (rhesus, cynomolgus, and African green monkey) are different from those determined with human liver microsomes. In contrast to the high affinity-high capacity (low Km-high Vmax) characteristics of DF 4'-hydroxylation in humans, this reaction proceeded in all monkey species with catalytic efficiencies >20-fold lower. However, DF 5-hydroxylation, a negligible reaction in human liver microsomes, was kinetically favored in monkeys mainly due to the increased Vmax values. Chemical inhibitors (reversible or mechanism-based) selective to human CYP3A4 and CYP2C9 failed to differentiate monkey orthologs involved in DF hydroxylation. Immunoinhibition studies with monoclonal antibodies against human CYPs revealed the major contribution of CYP2C and CYP3A to 4'- and to 5-hydroxylation, respectively, in rhesus and cynomolgus liver microsomes. However, in African green monkeys, in addition to CYP2C, CYP3A also appeared to be involved in 4'-hydroxylation. Further studies with recombinant rhesus and African green monkey CYP2C and CYP3A enzymes (rhesus CYP2C75, 2C74, and 3A64; African green monkey CYP2C9agm and CYP3A4agm) confirmed the major role of CYP enzymes of these two subfamilies in DF 4'- and 5-hydroxylation. Clearly, while monkey CYP2C and 3A enzymes retain the same substrate selectivity towards DF hydroxylation as their human orthologs, their altered catalytic efficiency and response to chemical inhibitors may indicate different structural features of active sites as opposed to human orthologs.     

SIV Infection Impairs the Central Nervous System in Chinese Rhesus Macaques

The central nervous system (CNS) impairment is a consequence seen in SIV infection of rhesus macaques of Indian-origin, which is more common in infected macaques with rapid disease progression than in those with conventional disease progression. Here, we investigated the CNS damages in SIVmac239-infected Chinese rhesus macaques. We demonstrated that SIV infection of Chinese macaques could cause neuropathological impairments, which was evidenced by appearance of SIV-RNA positive cells, the infiltration of activated macrophages and abundant multinucleated giant cells (MNGCs) in the different regions of the brains. The animals with high viremia and short survival time (average of 16 weeks, rapid progression, RP) had severer neuropathological changes than those with conventional progression (CP). As compared with the RP animals, CP macaques had lower viremia and much longer survival time (average of 154 weeks). These findings indicate that SIVmac239 infection of Chinese rhesus macaque can be used as a suitable animal model and alternative resource for nueroAIDS research.     

Unusual metabolism of caffeine in the squirrel monkey

The chronic toxicity of caffeine observed with the squirrel monkey appears to be related to the long plasma half-life of caffeine in this species. A half-life of 11 hr was found following the administration of 5 mg/kg compared to 2.4 hr in the rhesus monkey (5 hr or less have previously been reported for the mouse, dog and man). The methylxanthines found in the tissues and urine of the squirrel monkey following caffeine administration were the same as those reported for other species. No difference in the metabolism of caffeine by a squirrel monkey showing a toxic response to 25 mg/kg/day and a monkey tolerating this dose could be determined. The squirrel monkey appears to have a unique deficit in its ability to catabolize caffeine to metabolites which can be effectively excreted.     

Effects of morphine sulfate on operant behavior in rhesus monkeys

The acute effects of morphine sulfate were assessed using a battery of complex food-reinforced operant tasks that included temporal response differentiation (TRD, n = 5), delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 9), incremental repeated acquisition (IRA, n = 9), and conditioned position responding (CPR, n = 7) tasks. Performance in these tasks is thought to depend upon specific brain functions such as time perception (TRD), learning (IRA), short-term memory and attention (DMTS), color and position discrimination (CPR), and motivation to work for food (PR). Morphine sulfate (0.1-5.6 mg/kg IV), given 15 min presession, produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses greater than or equal to 1.0 mg/kg for TRD when compared to saline injections. Accuracy was not consistently affected in any other task in the test battery. Response rates decreased or response latencies increased significantly at doses of 1.0 mg/kg and above for the PR task, at 3.0 mg/kg and above for the IRA and TRD tasks, and only at the highest dose 5.6 mg/kg in the CPR and DMTS tasks. Percent task completed was decreased following doses of 1.0 mg/kg and higher for the IRA, PR and TRD tasks, at doses of 3.0 mg/kg and higher for the DMTS task, and at the high dose of 5.6 mg/kg for the CPR task. These results indicate that in monkeys, the performance of operant tasks designed to model learning ability (IRA), time perception (TRD) and motivation (PR) are more sensitive to the disruptive effects of morphine than is performance in tasks designed to model short-term memory and attention (DMTS). The task which models color and position discrimination (CPR) was the least sensitive to disruption by morphine.     

Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats,guinea-pigs,beagles and rhesus monkeys

1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole, is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey.

2. After a single oral dosing of ¹⁴C-I (10mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 + 0.3% in rat, 46.9.1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey.

3. After a single i.v. dose of ¹⁴C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71.0.01 to 0.93.0.05 as the dose was increased from 0.2 to 20mg/kg.     

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) in the rat, mouse, rabbit, do, rhesus monkey, and man

The disposition and metabolism of 5-(4,5-dihydro-2-phenylbenz[e]indol-3-yl)salicylic acid (fendosal) a new salicylate-type analgesic, has been studied in the rat, mouse, rabbit, dog, rhesus monkey, and man. Animals were given single oral or parenteral doses at levels of 5, 10, or 50 mg/kg; human volunteers received 200 mg orally. In all species, virtually all radioactivity was excreted in the feces. Biliary excretion accounted for approximately 50% of an oral dose in the rat and dog. Enterohepatic circulation was demonstrated in the rat. The compound was fairly rapidly absorbed in all species except the rhesus monkey. The principal excretion products found in all species were unchanged fendosal and a monohydroxylated metabolite, the latter being present both in the free state and as a glucuronide. A minor metabolite, present only in man and rhesus monkey, was tentatively identified as a dihydroxylated metabolite. These compounds were, however, detected only in unpurified samples. During the isolation and purification procedure, oxidation occurred, resulting in the production of the corresponding dehydrogenated derivatives, which were the actual materials whose structures were elucidated.     

Visual recognition memory in squirrel monkeys: effects of serotonin antagonists on baseline and hypoxia-induced performance deficits.

Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral effects of AMI-193, a 5-HT(2A)- and dopamine D(2)-receptor antagonist, in the squirrel monkey

8-[3-(4-Fluorophenoxy) propyl]-1-phenyl-1,3,8-triazaspiro[4, 5]decan-4-one (AMI-193) was developed as a 5-HT(2A)-selective antagonist with in vivo activity suitable for behavioral studies. However, AMI-193 is a potent dopamine D(2)-receptor antagonist with low nanomolar affinity. Accordingly, D(2)-actions may contribute to its behavioral pharmacology. In the present study, the effects of AMI-193 on operant behavior were characterized in squirrel monkeys. In subjects trained under a fixed-interval (FI) schedule of stimulus termination, AMI-193 (0.003-0.01 mg/kg) dose-dependently decreased response rate. When administered in combination with cocaine (0.03-3. 0 mg/kg) or the selective dopamine uptake inhibitor, GBR 12909 (0. 03-3.0 mg/kg), the rate-decreasing effects of AMI-193 were reversed by both dopamine indirect agonists. In drug-discrimination experiments, AMI-193 (0.003 and 0.01 mg/kg) attenuated the discriminative-stimulus effects of cocaine. AMI-193 (0.003 and 0.01 mg/kg) also reduced response rate under a second-order schedule of i. v. self-administration of cocaine (0.1 mg/infusion). The profile of behavioral effects and drug interactions observed in the present study, in conjunction with the relatively high affinity of AMI-193 for dopamine D(2) receptors, suggests that its D(2)-antagonist effects play a prominent role in the behavioral pharmacology of AMI-193.     

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional‐poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre‐hospital and/or mass‐casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25‐200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25‐100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25‐25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50‐200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24‐72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre‐hospital or mass‐casualty emergency medical treatment.     

Pharmacokinetics of ciprofloxacin. 1st communication: absorption, concentrations in plasma, metabolism and excretion after a single administration of [14C]ciprofloxacin in albino rats and rhesus monkeys

The absorption, disposition, metabolism and excretion of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-[U-14C]piperazinyl)-3- quinoline carboxylic acid (ciprofloxacin, Bay o 9867; designated tradename: Ciprobay) were studied following a single intraduodenal (rat), oral and intravenous (rat, monkey) administration, respectively, in the dose range 5 to 30 mg/kg body weight. Ciprofloxacin was absorbed partially (30 to 40%) in both species. Peak plasma concentrations of radioactivity were measured approximately 1 h (rat) or 2 h (monkey) after oral dosing. Terminal half-lives ranging from 26 to 44 h were determined for the elimination of radioactivity from the plasma (observation time up to 48 h after dosing). Nearly identical concentrations of the unchanged drug and total radioactivity were found during the first 7 or 8 h for the monkey after intravenous injection and for the rat also after oral administration, respectively. After reaching maximum concentration of 0.25 microgram/ml after administration of 5 mg/kg to rats and 0.88 microgram/ml after dosing with 30 mg/kg to a rhesus monkey, the unchanged drug was eliminated from plasma corresponding to half-lives ranging from 3 h (rat) and 4.4 h (monkey). The radioactivity was rapidly and completely excreted in both species. After intravenous administration about 51% (rat) and 61% (monkey), respectively, was excreted via the kidney. After oral dosing renal excretion amounted to 6-14% (rat) and 30% (monkey), respectively. Maximum residues in the body (exclusive gastrointestinal tract) of 1% of dose occurred in both species. In urine and feces of rats predominantly the unchanged drug and a conjugate were detected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of rolipram in the rhesus and cynomolgus monkeys, the rat and the rabbit. Studies on species differences

1. The pharmacokinetics of rolipram were studied in rat, rabbit, rhesus monkey and cynomolgus monkey using 14C- or 3H-labelled rolipram and a radioimmunoassay for measurement of unchanged drug. 2. Rolipram was rapidly and completely absorbed after oral doses of up to 50 mg/kg. Bioavailability was 0.1% in rhesus monkey, 3.7% in cynomolgus monkey, 3.6% in rabbit, 35% in rat, and 75% in man. 3. Rolipram was able to pass the blood-brain barrier achieving concentrations in brain twice those in plasma. 4. Plasma levels of the unchanged drug declined with a similar half-life of 1-3 h in all species investigated. In the rat, there were indications for a different clearance of the two rolipram enantiomers. 5. Labelled rolipram was excreted rapidly and completely. The main route of elimination was via the urine.     

The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys

IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 microM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15-10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.