Pentazocine, metabolism

Fig. 10. Pentazocine metabolic pathways and urinary excretion products in man and monkey.

A study in which pentazocine was used to supplement nitrous oxide relaxant anaesthesia found that patients who came from an urban environment needed about 50% more pentazocine than those who lived in the country (3.6 micrograms/kg per minute compared with 2.4 micrograms/kg per minute). Roughly the same difference was seen between those who smoked and those who did not (3.8 micrograms/kg per minute compared with 2.5 micrograms/kg per minute). In another study it was found that pentazocine metabolism was 40% higher in smokers than in non-smok-... 

Keeri-Szanto H Pomeroy JR. Atmospheric pollution and pentazocine metabolism. Lancet (1971) i, 947-9. 

Pentazocine has been successfully used to relieve labour pain [201] and its obstetric use in place of pethidine is favoured by,its apparent inferior ability to pass the placental barrier [206]. A clinical trial of (+)- and (-)-pentazocine adds to the rare number of examples in which optical enantiomorphs have been evaluated [207]. In post-operative patients, response to 60 mg of the dextro isomer was less than that to 5 mg of morphine, while 25—29 mg of (-)-pentazocine was as effective as 10 mg of morphine. Hence most of the activity of the race-mate resides in the laevo isomer, as anticipated from results in animals [208]. Several studies of the distribution, excretion and metabolism of pentazocine have been made. Peak levels of the tritium-labelled drug (and its c/s-3-chloroallyl analogue) were present in the C.N.S. of a cat within 40 minutes of intramuscular administration [209], the comparable figure for morphine being 2 hours [210]. 

Absorption of pentazocine following oral administration is rapid. The onset of action occurs within approximately 15 minutes, and the half-life is 2 to 3 hours. Pentazocine is extensively metabolized in the liver and thus has a high first-pass effect following oral administration its half-life differs considerably from patient to patient. Oxidation of the methyl groups followed by conjugation to glucuronides in the liver terminates the effects of pentazocine. Excretion occurs through the kidney. 

Pharmacokinetic properties Pentazocine is orally bioavailable but there is a high degree of fluctuation in resorption. The compound is rapidly and extensively metabolized. Metabolites are formed by oxidative demethylation of the methyl residues of the dimethylallyl group and by glucuronidation (Berkowitz, 1973). The metabolic pathway of pentazocine is shown in scheme 42. 

The absorption, distribution, metabolism and excretion of pentazocine have been widely studied in both man and animal species. Early work was carried out by three major groups Pittman and coworkers, Beckett and coworkers and Berkowitz,... 

Way and coworkers. Reviews of metabolism (51) and pharmacokinetics (97) of pentazocine have been published. The effect of route of administration on the disposition of pentazocine has been explored (27, 9,75,85,86). The metabolic pathways available to pentazocine are outlined in Figure 10. Also shown are urinary excretion data for the metabolites expressed as percent of administered dose. 

Pifferences in pentazocine disposition in smokers and nonsmokers has been observed with the former metabolizing 40% more rapidly(98).The effect of cirrhosis on pentazocine bioavailability has also been studied. A 46% decrease in clearance and a 233-278% increase in bioavailability of pentazocine for these patients was found (84,89). Other disposition studies have been done on post-operative patients (59), mother and infant at time of birth (99) and normal subjects with circadian variation (36). 

Studies of pentazocine biological disposition in animals consist of tissue uptake (26,52,58,65, 68,79), blood level (50,61,7 0 and urine level determinations (88). While animal metabolic pathways identified (39. 0,70) are similar to those found in man, additional products have been demonstrated. In the rat 9-methoxypentazocine (or its 8-methoxy-9-hydroxy isomer), 8,9 (or 9.8)-methoxy-hydroxy metabolite of the cis-alcohol product and 8,9 (or 9,8)-methoxyhydroxy metabolite of the transalcohol product were found. Pharmacokinetic studies have been done in rhesus monkey (66) and in the dog (35t5 63) Typical plasma half-lives measured in dog plasma are 1.2-1.6 hours. A day-night variation was also observed in the calculated parameters (35). 

SSRIs OPIOIDS 1. Possible 1 analgesic effect of oxycodone and tramadol 2. T serotonin effects, including possible cases of serotonin syndrome, when opioids (oxycodone, pethidine, pentazocine, tramadol) are co-administered with SSRIs (fluoxetine and sertraline) 3. SSRIs may t codeine, fentanyl, methadone, pethidine and tramadol levels 1. Uncertain. Paroxetine inhibits CYP2D6, which is required to produce the active form of tramadol. 2. Uncertain 3. SSRIs inhibit CYP2D6-mediated metabolism of these opioids 1. Consider using an alternative opioid 2. Look for signs of T serotonin activity, particularly on initiating therapy 3. Watch for excessive narcotization... 

Cigarette smoke contains minute amounts of polycyclic aromatic hydrocarbons, such as benzol nr pyrene. which are potent inducers of microsomal cytochrome P-4S0 enzymes. This induction increases the oxidation of some drugs in nnokets. For example, theophylline is metabolized more rapidly in smokers than in nonsmokers. This difference is reflected in the marked difference in the plasma half-life of theophylline between smokers (r /2 4.1 hours) and non-smokers u A 7.2 hours). Other drugs, such as phenacetin. pentazocine. and propoxyphene, also reportedly undergo more rapid metabolism in smokers than in nonsmokers. " ... 

The liver is the most important site of presystemic elimination because of high levels of drug-metabolizing enzymes, its ability to rapidly metabolize different types of drugs, and its unique anatomical location. The following are selected examples of drugs that are subject to considerable hepatic first-pass metabolism the 3-blockers propranolol and metoprolol the analgesics propoxyphene, meperidine, and pentazocine the antidepressants imipramine and nortriptyline and the antiarrhythmic lidocaine. 

Bioavailability and first-pass metabolism of oral pentazocine in man. Clin Pharmacol Ther 1977 22 888-892 with permission.)... 

The elimination half-life of pentazocine is approximately 4 hours after parenteral dosage and 3 hours after oral dosage. Bioavailability after oral dose is only 20 to 50% because of first-pass metabolism. Pentazocine is metabolized extensively in the liver and is excreted via the urinary tract. The major metabolites are 3-O-conjugates and hydroxylation of the terminal methyl groups of the N-substituent. All metabolites are inactive. 

It is thought that tobacco smoke contains compounds that increase the activity of the liver enzymes concerned with the metabolism of dextropropoxyphene, pentazocine and other opioids, which increases their metabolism, decreases their levels and diminishes their effectiveness as analgesics. However, former smokers have also been found to have increased opioid requirements and it has been suggested that smoking might have an effect on pain perception and/or opioid response, or that nicotine addiction and opioid requirements may be genetically linked. ... 

B. Benzomorphans - Clinical trials of the d 1 isomers of pentazocine (k) have shown "16 th both analgesic activity and side effects reside in the levo-isomer. Other trials, double-blind in many patients, confirm" 7,18 the activity of the compound at about one-third that of morphine, while measurements of respiratory depression in treated patients suggest" 9,20 this to be less than morphine at equianalgesic doses. The oral absorption has been determined2 1 and metabolic breakdown found22 to occur predominantly at the terminal methyl groups of the side chain. Reports of addiction to the injected form of pentazocine have been published ,24,25 including one to the oral form. 

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